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  • 1. Agudo, Marta
    et al.
    Pérez-Marín, Maria Cruz
    Lönngren, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Sobrado, Paloma
    Conesa, Ana
    Cánovas, Isabel
    Salinas-Navarro, Manuel
    Miralles-Imperial, Jaime
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Vidal-Sanz, Manuel
    Time course profiling of the retinal transcriptome after optic nerve transection and optic nerve crush2008In: Molecular Vision, ISSN 1090-0535, E-ISSN 1090-0535, Vol. 14, 1050-1063 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    A time-course analysis of gene regulation in the adult rat retina after intraorbital nerve crush (IONC) and intraorbital nerve transection (IONT).

    METHODS:

    RNA was extracted from adult rat retinas undergoing either IONT or IONC at increasing times post-lesion. Affymetrix RAE230.2 arrays were hybridized and analyzed. Statistically regulated genes were annotated and functionally clustered. Arrays were validated by means of quantative reverse transcription polymerase chain reaction (qRT-PCR) on ten regulated genes at two times post-lesion. Western blotting and immunohistofluorescence for four pro-apoptotic proteins were performed on naïve and injured retinas. Finally, custom signaling maps for IONT- and IONC-induced death response were generated (MetaCore, Genego Inc.).

    RESULTS:

    Here we show that over time, 3,219 sequences were regulated after IONT and 1,996 after IONC. Out of the total of regulated sequences, 1,078 were commonly regulated by both injuries. Interestingly, while IONT mainly triggers a gene upregulation-sustained over time, IONC causes a transitory downregulation. Functional clustering identified the regulation of high interest biologic processes, most importantly cell death wherein apoptosis was the most significant cluster. Ten death-related genes upregulated by both injuries were used for array validation by means of qRT-PCR. In addition, western blotting and immunohistofluorescence of total and active Caspase 3 (Casp3), tumor necrosis factor receptor type 1 associated death domain (TRADD), tumor necrosis factor receptor superfamily member 1a (TNFR1a), and c-fos were performed to confirm their protein regulation and expression pattern in naïve and injured retinas. These analyses demonstrated that for these genes, protein regulation followed transcriptional regulation and that these pro-apoptotic proteins were expressed by retinal ganglion cells (RGCs). MetaCore-based death-signaling maps show that several apoptotic cascades were regulated in the retina following optic nerve injury and highlight the similarities and differences between IONT and IONC in cell death profiling.

    CONCLUSIONS:

    This comprehensive time course retinal transcriptome study comparing IONT and IONC lesions provides a unique valuable tool to understand the molecular mechanisms underlying optic nerve injury and to design neuroprotective protocols.

  • 2. Apostolova, Galina
    et al.
    Dorn, Roland
    Ka, Sojeong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Lundeberg, Joakim
    Liser, Keren
    Hakim, Vicky
    Brodski, Claude
    Michaelidis, Theologos M.
    Dechant, Georg
    Neurotransmitter phenotype-specific expression changes in developing sympathetic neurons2007In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 35, no 3, 397-408 p.Article in journal (Refereed)
    Abstract [en]

    During late developmental phases individual sympathetic neurons undergo a switch from noradrenergic to cholinergic neurotransmission. This phenomenon of plasticity depends on target-derived signals in vivo and is triggered by neurotrophic factors in neuronal cultures. To analyze genome-wide expression differences between the two transmitter phenotypes we employed DNA microarrays. RNA expression profiles were obtained from chick paravertebral sympathetic ganglia, treated with neurotrophin 3, glial cell line-derived neurotrophic factor or ciliary neurotrophic factor, all of which stimulate cholinergic differentiation. Results were compared with the effect of nerve growth factor, which functions as a pro-noradrenergic stimulus. The gene set common to all three comparisons defined the noradrenergic and cholinergic synexpression groups. Several functional categories, such as signal transduction, G-protein-coupled signaling, cation transport, neurogenesis and synaptic transmission, were enriched in these groups. Experiments based on the prediction that some of the identified genes play a role in the neurotransmitter switch identified bone morphogenetic protein signaling as an inhibitor of cholinergic differentiation.

  • 3. Ayer-LeLievre, C
    et al.
    Olson, L
    Ebendal, T
    Hallböök, F
    Persson, H
    Nerve growth factor mRNA and protein in the testis and epididymis of mouse and rat.1988In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 85, no 8, 2628-32 p.Article in journal (Refereed)
    Abstract [en]

    In situ hybridization using beta-nerve growth factor (NGF) DNA probes was used to demonstrate NGF mRNA in spermatocytes and early spermatids of adult mouse. NGF mRNA-containing cells were also identified in the epithelium of convoluted ducts in mouse corpus epididymidis. Blot-hybridization analysis of RNA prepared from mouse testis and epididymis as well as from rat epididymis confirmed the presence of a 1.3-kilobase (kb) NGF mRNA in these tissues. In the rat testis, however, only a 1.5-kb NGF mRNA was found, corresponding in size to a minor NGF mRNA detected in the rat brain, heart, and epididymis. By using affinity-purified anti-NGF antibodies, NGF-like immunoreactivity was observed in germ cells of rat and mouse testis and in the lumen of epididymis. Extracts of both mouse epididymis and testis stimulated fiber outgrowth in cultured sympathetic ganglia, and the effect was blocked by antibodies to mouse NGF. A two-site enzyme immunoassay showed the presence of 10 and 70 ng of NGF per g of tissue in the mouse testis and epididymis, respectively. Furthermore, RNA blot analysis showed the presence of mRNA for the NGF receptor in mouse testis. These results suggest a nonneurotrophic role for NGF in the male reproductive system, possibly in survival maturation and/or motility of spermatozoa.

  • 4.
    Bakall, Benjamin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mayordomo, Raquel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Analysis of subcellular location of bestrophin in transfected RPE cell lines2000In: Gene Function and Disease, ISSN 1438-7506, E-ISSN 1438-826X, Vol. 1, no 3-4, 128-133 p.Article in journal (Refereed)
    Abstract [en]

    Best macular dystrophy is an autosomal dominant disease leading to macular degeneration and subsequent impaired vision. The disease has juvenile onset and affects the retinal pigment epithelium and adjacent photoreceptors. There are histopathological similarities between Best macular dystrophy (BMD) and age-related macular degeneration (AMD) with accumulation of lipofuscin in the outer retina. Recently, we identified the gene VMD2 causing Best macular dystrophy. The VMD2 gene has unknown function and there are no similarities between the VMD2 product, called bestrophin, and other proteins with known function. In order to gain more knowledge about the function of bestrophin we investigated its subcellular localization. DNA constructs encoding the bestrophin protein fused to the green fluorescent protein (GFP) or a c-myc tag were transiently expressed in COS-7 cells or retinal pigment epithelium cells. The observed pattern of bestrophin fusion protein was spotted and mainly perinuclear, well corresponding to the endoplasmic reticulum (ER), which was also suggested when counterstaining with an ER probe. Probes for other organelles had a different localization pattern compared to bestrophin. In conclusion, the results indicate that bestrophin is located to the endoplasmic reticulum.

  • 5.
    Blixt, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    A regulatory sequence from the retinoid X receptor gamma gene directs expression to horizontal cells and photoreceptors in the embryonic chicken retina2016In: Molecular Vision, ISSN 1090-0535, E-ISSN 1090-0535, Vol. 22, 1405-1420 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Combining techniques of episomal vector gene-specific Cre expression and genomic integration using the piggyBac transposon system enables studies of gene expression-specific cell lineage tracing in the chicken retina. In this work, we aimed to target the retinal horizontal cell progenitors. METHODS: A 208 bp gene regulatory sequence from the chicken retinoid X receptor gammagene (RXRgamma208) was used to drive Cre expression. RXRgamma is expressed in progenitors and photoreceptors during development. The vector was combined with a piggyBac "donor" vector containing a floxed STOP sequence followed by enhanced green fluorescent protein (EGFP), as well as a piggyBac helper vector for efficient integration into the host cell genome. The vectors were introduced into the embryonic chicken retina with in ovo electroporation. Tissue electroporation targets specific developmental time points and in specific structures. RESULTS: Cells that drove Cre expression from the regulatory RXRgamma208 sequence excised the floxed STOP-sequence and expressed GFP. The approach generated a stable lineage with robust expression of GFP in retinal cells that have activated transcription from the RXRgamma208 sequence. Furthermore, GFP was expressed in cells that express horizontal or photoreceptor markers when electroporation was performed between developmental stages 22 and 28. Electroporation of a stage 12 optic cup gave multiple cell types in accordance with RXRgamma gene expression in the early retina. CONCLUSIONS: In this study, we describe an easy, cost-effective, and time-efficient method for testing regulatory sequences in general. More specifically, our results open up the possibility for further studies of the RXRgamma-gene regulatory network governing the formation of photoreceptor and horizontal cells. In addition, the method presents approaches to target the expression of effector genes, such as regulators of cell fate or cell cycle progression, to these cells and their progenitor.

  • 6.
    Blixt, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Lineage tracing of horizontal and photoreceptor cells in the embryonic chicken retina2016In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 57, no 12Article in journal (Refereed)
  • 7.
    Blixt, Martin K. E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Shirazi Fard, Shahrzad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    All-Ericsson, C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Adding another piece to the retinoblastoma puzzle2015In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 6, e1957Article in journal (Refereed)
  • 8.
    Boije, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Edqvist, Per-Henrik D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Horizontal cell progenitors arrest in G2-phase and undergo terminal mitosis on the vitreal side of the chick retina2009In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 330, no 1, 105-113 p.Article in journal (Refereed)
    Abstract [en]

    We have addressed the question when horizontal cells in the chick retina are generated and undergo their terminal mitosis. Horizontal cell progenitors replicate their DNA early and migrate bi-directionally to the horizontal cell layer. It was hypothesized that the cells undergo mitosis directly after replication and migrate as post-mitotic transition cells before differentiating to horizontal cells. However, our results show that cells expressing markers for the axon-bearing and the axon-less subtypes of horizontal cells undergo terminal mitosis while residing on the vitreal side of the retina. By combining horizontal cell transcription factors Lim1, Isl1 and Prox1 labeling with phospho-histone H3, a marker for mitosis, we demonstrate that all or a clear majority of vitreal mitoses are undertaken by the horizontal cell committed progenitors. The pattern of cells that incorporated the thymidine analogue EdU implied that the progenitors replicated their genome while migrating towards the vitreal side. Upon arrival to the vitreal retina they become arrested for about two days prior to mitosis. Hence, cells expressing horizontal cell markers are arrested in G2-phase on the vitreal side of the retina. These results support the existence of committed progenitors that give rise to horizontal cells and that those cells become arrested in G2-phase before undergoing terminal mitosis on the vitreal side of the retina followed by migration to the horizontal cell layer. The results also indicate that the regulation of the transition from G2-phase to mitosis is important for the development of these committed progenitor cells.

  • 9.
    Boije, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Edqvist, Per-Henrik D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Temporal and spatial expression of transcription factors FoxN4, Ptf1a, Prox1, Isl1 and Lim1 mRNA in the developing chick retina2008In: Gene Expression Patterns, ISSN 1567-133X, E-ISSN 1872-7298, Vol. 8, no 2, 117-123 p.Article in journal (Refereed)
    Abstract [en]

    Transcription factors are pivotal in regulating cell fate and development. We analyzed five transcription factors - FoxN4, Ptf1a, Prox1, Isl1 and Lim1 - with putative functions in the formation of early-generated retinal interneurons. A full-length chicken FoxN4 cDNA was characterized and in situ as well as RT-PCR showed that FoxN4 expression commenced already in the stage 12-14 optic vesicles. Ptf1a, Prox1, Isl1 and Lim1 expression appeared later by stage 20-24, concomitant with the first post-mitotic ganglion-, amacrine- and horizontal cells. The FoxN4 and Ptf1a expression was transient with peak levels by stage 32-35. Expression disappeared as the retinal progenitor cells differentiated. Prox1, Isl1 and Lim1 expression remained in several differentiated cells including the horizontal cells. The order of expression supports a scheme where Ptf1a and Prox1 is downstream of FoxN4 and that FoxN4 and Ptf1a have transient roles during fate specification while Prox1, Isl1 and Lim1 have roles that are important for the generation of the neuronal subtypes.

  • 10.
    Boije, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Fard, Shahrzad Shirazi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Horizontal Cells, the Odd Ones Out in the Retina, Give Insights into Development and Disease2016In: Frontiers in Neuroanatomy, ISSN 1662-5129, E-ISSN 1662-5129, Vol. 10, 77Article, review/survey (Refereed)
    Abstract [en]

    Thorough investigation of a neuronal population can help reveal key aspects regarding the nervous system and its development. The retinal horizontal cells have several extraordinary features making them particularly interesting for addressing questions regarding fate assignment and subtype specification. In this review we discuss and summarize data concerning the formation and diversity of horizontal cells, how morphology is correlated to molecular markers, and how fate assignment separates the horizontal lineage from the lineages of other retinal cell types. We discuss the novel and unique features of the final cell cycle of horizontal cell progenitors and how they may relate to retinoblastoma carcinogenesis.

  • 11.
    Boije, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Harun-Or-Rashid, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Lee, Yu-Jen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Imsland, Freyja
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bruneau, Nicolas
    Vieaud, Agathe
    Gourichon, David
    Tixier-Boichard, Michèle
    Bed’hom, Bertrand
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Sonic Hedgehog-Signalling Patterns the Developing Chicken Comb as Revealed by Exploration of the Pea-comb Mutation2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, e50890- p.Article in journal (Refereed)
    Abstract [en]

    The genetic basis and mechanisms behind the morphological variation observed throughout the animal kingdom is stillrelatively unknown. In the present work we have focused on the establishment of the chicken comb-morphology byexploring the Pea-comb mutant. The wild-type single-comb is reduced in size and distorted in the Pea-comb mutant. Peacombis formed by a lateral expansion of the central comb anlage into three ridges and is caused by a mutation in SOX5,which induces ectopic expression of the SOX5 transcription factor in mesenchyme under the developing comb. Analysis ofdifferential gene expression identified decreased Sonic hedgehog (SHH) receptor expression in Pea-comb mesenchyme. Byexperimentally blocking SHH with cyclopamine, the wild-type single-comb was transformed into a Pea-comb-likephenotype. The results show that the patterning of the chicken comb is under the control of SHH and suggest that ectopicSOX5 expression in the Pea-comb change the response of mesenchyme to SHH signalling with altered combmorphogenesis as a result. A role for the mesenchyme during comb morphogenesis is further supported by the recentfinding that another comb-mutant (Rose-comb), is caused by ectopic expression of a transcription factor in combmesenchyme. The present study does not only give knowledge about how the chicken comb is formed, it also adds to ourunderstanding how mutations or genetic polymorphisms may contribute to inherited variations in the human face.

  • 12.
    Boije, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Ring, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Fard, Shahrzad Shirazi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Grundberg, Ida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallbook, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Alternative Splicing of the Chromodomain Protein Morf4l1 Pre-mRNA Has Implications on Cell Differentiation in the Developing Chicken Retina2013In: Journal of Molecular Neuroscience, ISSN 0895-8696, E-ISSN 1559-1166, Vol. 51, no 2, 615-628 p.Article in journal (Refereed)
    Abstract [en]

    The proliferation, cell cycle exit and differentiation of progenitor cells are controlled by several different factors. The chromodomain protein mortality factor 4-like 1 (Morf4l1) has been ascribed a role in both proliferation and differentiation. Little attention has been given to the existence of alternative splice variants of the Morf4l1 mRNA, which encode two Morf41l isoforms: a short isoform (S-Morf4l1) with an intact chromodomain and a long isoform (L-Morf4l1) with an insertion in or in the vicinity of the chromodomain. The aim of this study was to investigate if this alternative splicing has a function during development. We analysed the temporal and spatial distribution of the two mRNAs and over-expressed both isoforms in the developing retina. The results showed that the S-Morf4l1 mRNA is developmentally regulated. Over-expression of S-Morf4l1 using a retrovirus vector produced a clear phenotype with an increase of early-born neurons: retinal ganglion cells, horizontal cells and cone photoreceptor cells. Over-expression of L-Morf4l1 did not produce any distinguishable phenotype. The over-expression of S-Morf4l1 but not L-Morf4l1 also increased apoptosis in the infected regions. Our results suggest that the two Morf4l1 isoforms have different functions during retinogenesis and that Morf4l1 functions are fine-tuned by developmentally regulated alternative splicing. The data also suggest that Morf4l1 contributes to the regulation of cell genesis in the retina.

  • 13.
    Boije, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Ring, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Lopez-Gallardo, Meritxell
    Prada, Carmen
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Pax2 Is Expressed in a Subpopulation of Muller Cells in the Central Chick Retina2010In: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 239, no 6, 1858-1866 p.Article in journal (Refereed)
    Abstract [en]

    Muller cells in the chick retina are generally thought to be a homogeneous population. We show that the transcription factor Pax2 is expressed by Muller cells in the central chick retina and its expression was first observed at stage 32 (embryonic day [E] 7.5). Birth-dating indicated that the majority of Pax2-positive Muller cells are generated between stage 29 and 33 (E5.5-E8). At stage 42 (E16), several Muller cell markers, such as Sox2 and 2M6, had reached the peripheral retina, while the Pax2 labeling extended approximately half-way. A similar pattern was maintained in the 6-month-old chicken. Neither the Pax2-positive nor the Pax2-negative Muller cells could be specifically associated to proliferative responses in the retina induced by growth factors or N-methyl-D-aspartate. Pax2 was not detected in Muller cells in mouse, rat, guinea-pig, rabbit, or pig retinas; but the zebrafish retina displayed a similar pattern of central Pax2-expressing Muller cells.

  • 14.
    Boije, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Shirazi Fard, S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Ring, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Forkheadbox N4 (FoxN4) triggers context-dependent differentiation in the developing chick retina and neural tube2013In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 85, no 1-2, 11-19 p.Article in journal (Refereed)
    Abstract [en]

    FoxN4, a forkhead box transcription factor, is expressed in the chicken eye field and in retinal progenitor cells (RPCs) throughout development. FoxN4 labelling overlapped with that of Pax6 and Sox2, two crucial transcription factors for RPCs. Later, during neurogenesis in the retina, some cells were intensely and transiently labelled for FoxN4. These cells co-labelled for Lim1, a transcription factor expressed in early-born horizontal cells. The result suggests that high levels of FoxN4 combined with expression of Lim1 define a population of RPCs committed to the horizontal cell fate prior to their last apical mitosis. As these prospective horizontal cells develop, their FoxN4 expression is down-regulated. Previous results suggested that FoxN4 is important for the generation of horizontal and amacrine cells but that it is not sufficient for the generation of horizontal cells (Li et al., 2004). We found that over-expression of FoxN4 in embryonic day 3 chicken retina could activate horizontal cell markers Prox1 and Lim1, and that it generated numerous and ectopically located horizontal cells of both main subtypes. However, genes expressed in photoreceptors, amacrine and ganglion cells were also activated, indicating that FoxN4 triggered the expression of several differentiation factors. This effect was not exclusive for the retina but was also seen when FoxN4 was over-expressed in the mesencephalic neural tube. Combining the results from over-expression and wild-type expression data we suggest a model where a low level of FoxN4 is maintained in RPCs and that increased levels during a restricted period trigger neurogenesis and commitment of RPCs to the horizontal cell fate.

  • 15. Burke, R D
    et al.
    Angerer, L M
    Elphick, M R
    Humphrey, G W
    Yaguchi, S
    Kiyama, T
    Liang, S
    Mu, X
    Agca, C
    Klein, W H
    Brandhorst, B P
    Rowe, M
    Wilson, K
    Churcher, A M
    Taylor, J S
    Chen, N
    Murray, G
    Wang, D
    Mellott, D
    Olinski, R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Thorndyke, M C
    A genomic view of the sea urchin nervous system2006In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 300, no 1, 434-460 p.Article in journal (Other academic)
    Abstract [en]

    The sequencing of the Strongylocentrotus purpuratus genome provides a unique opportunity to investigate the function and evolution of neural genes. The neurobiology of sea urchins is of particular interest because they have a close phylogenetic relationship with chordates, yet a distinctive pentaradiate body plan and unusual neural organization. Orthologues of transcription factors that regulate neurogenesis in other animals have been identified and several are expressed in neurogenic domains before gastrulation indicating that they may operate near the top of a conserved neural gene regulatory network. A family of genes encoding voltage-gated ion channels is present but, surprisingly, genes encoding gap junction proteins (connexins and pannexins) appear to be absent. Genes required for synapse formation and function have been identified and genes for synthesis and transport of neurotransmitters are present. There is a large family of G-protein-coupled receptors, including 874 rhodopsin-type receptors, 28 metabotropic glutamate-like receptors and a remarkably expanded group of 161 secretin receptor-like proteins. Absence of cannabinoid, lysophospholipid and melanocortin receptors indicates that this group may be unique to chordates. There are at least 37 putative G-protein-coupled peptide receptors and precursors for several neuropeptides and peptide hormones have been identified, including SALMFamides, NGFFFamide, a vasotocin-like peptide, glycoprotein hormones and insulin/insulin-like growth factors. Identification of a neurotrophin-like gene and Trk receptor in sea urchin indicates that this neural signaling system is not unique to chordates. Several hundred chemoreceptor genes have been predicted using several approaches, a number similar to that for other animals. Intriguingly, genes encoding homologues of rhodopsin, Pax6 and several other key mammalian retinal transcription factors are expressed in tube feet, suggesting tube feet function as photosensory organs. Analysis of the sea urchin genome presents a unique perspective on the evolutionary history of deuterostome nervous systems and reveals new approaches to investigate the development and neurobiology of sea urchins.

  • 16. Chavarría, Teresa
    et al.
    Valenciano, Ana I.
    Mayordomo, Raquel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Egea, Joaquim
    Comella, Joan X.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    de Pablo, Flora
    de la Rosa, Enrique J.
    Differential, age-dependent MEK-ERK and PI3K-Akt activation by insulin acting as a survival factor during embryonic retinal development2007In: Developmental Neurobiology, ISSN 1932-8451, E-ISSN 1932-846X, Vol. 67, no 13, 1777-1788 p.Article in journal (Refereed)
    Abstract [en]

    Programmed cell death is a genuine developmental process of the nervous system, affecting not only projecting neurons but also proliferative neuroepithelial cells and young neuroblasts. The embryonic chick retina has been employed to correlate in vivo and in vitro studies on cell death regulation. We characterize here the role of two major signaling pathways, PI3K-Akt and MEK-ERK, in controlled retinal organotypic cultures from embryonic day 5 (E5) and E9, when cell death preferentially affects proliferating neuroepithelial cells and ganglion cell neurons, respectively. The relative density of programmed cell death in vivo was much higher in the proliferative and early neurogenic stages of retinal development (E3-E5) than during neuronal maturation and synaptogenesis (E8-E19). In organotypic cultures from E5 and E9 retinas, insulin, as the only growth factor added, was able to completely prevent cell death induced by growth factor deprivation. Insulin activated both the PI3K-Akt and the MEK-ERK pathways. Insulin survival effect, however, was differentially blocked at the two stages. At E5, the effect was blocked by MEK inhibitors, whereas at E9 it was blocked by PI3K inhibitors. The cells which were found to be dependent on insulin activation of the MEK-ERK pathway at E5 were mostly proliferative neuroepithelial cells. These observations support a remarkable specificity in the regulation of early neural cell death.

  • 17.
    Dorshorst, Ben
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Harun-Or-Rashid, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Bagherpoor, Alireza Jian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Rubin, Carl-Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ashwell, Chris
    Gourichon, David
    Tixier-Boichard, Michèle
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Andersson, Leif
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    A Genomic Duplication is Associated with Ectopic Eomesodermin Expression in the Embryonic Chicken Comb and Two Duplex-comb Phenotypes2015In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 3, e1004947Article in journal (Refereed)
    Abstract [en]

    Duplex-comb (D) is one of three major loci affecting comb morphology in the domestic chicken. Here we show that the two Duplex-comb alleles, V-shaped (D*V) and Buttercup (D*C), are both associated with a 20 Kb tandem duplication containing several conserved putative regulatory elements located 200 Kb upstream of the eomesodermin gene (EOMES). EOMES is a T-box transcription factor that is involved in mesoderm specification during gastrulation. In D*V and D*C chicken embryos we find that EOMES is ectopically expressed in the ectoderm of the comb-developing region as compared to wild-type embryos. The confinement of the ectopic expression of EOMES to the ectoderm is in stark contrast to the causal mechanisms underlying the two other major comb loci in the chicken (Rose-comb and Pea-comb) in which the transcription factors MNR2 and SOX5 are ectopically expressed strictly in the mesenchyme. Interestingly, the causal mutations of all three major comb loci in the chicken are now known to be composed of large-scale structural genomic variants that each result in ectopic expression of transcription factors. The Duplex-comb locus also illustrates the evolution of alleles in domestic animals, which means that alleles evolve by the accumulation of two or more consecutive mutations affecting the phenotype. We do not yet know whether the V-shaped or Buttercup allele correspond to the second mutation that occurred on the haplotype of the original duplication event.

  • 18.
    Dorshorst, Ben
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Molin, Anna-Maja
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Anna M.
    Stromstedt, Lina
    Pham, Manh-Hung
    Chen, Chih-Feng
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Ashwell, Chris
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    A Complex Genomic Rearrangement Involving the Endothelin 3 Locus Causes Dermal Hyperpigmentation in the Chicken2011In: PLoS Genetics, ISSN 1553-7390, Vol. 7, no 12, e1002412- p.Article in journal (Refereed)
    Abstract [en]

    Dermal hyperpigmentation or Fibromelanosis (FM) is one of the few examples of skin pigmentation phenotypes in the chicken, where most other pigmentation variants influence feather color and patterning. The Silkie chicken is the most widespread and well-studied breed displaying this phenotype. The presence of the dominant FM allele results in extensive pigmentation of the dermal layer of skin and the majority of internal connective tissue. Here we identify the causal mutation of FM as an inverted duplication and junction of two genomic regions separated by more than 400 kb in wild-type individuals. One of these duplicated regions contains endothelin 3 (EDN3), a gene with a known role in promoting melanoblast proliferation. We show that EDN3 expression is increased in the developing Silkie embryo during the time in which melanoblasts are migrating, and elevated levels of expression are maintained in the adult skin tissue. We have examined four different chicken breeds from both Asia and Europe displaying dermal hyperpigmentation and conclude that the same structural variant underlies this phenotype in all chicken breeds. This complex genomic rearrangement causing a specific monogenic trait in the chicken illustrates how novel mutations with major phenotypic effects have been reused during breed formation in domestic animals.

  • 19. Ebendal, T
    et al.
    Söderström, S
    Hallböök, F
    Ernfors, P
    Ibáñez, C F
    Persson, H
    Wetmore, C
    Strömberg, I
    Olson, L
    Human nerve growth factor: biological and immunological activities, and clinical possibilities in neurodegenerative disease.1991In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 296, 207-25 p.Article in journal (Refereed)
  • 20.
    Edqvist, Per-Henrik D
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Lek, Madelen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Boije, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Lindbäck, Sarah M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Axon-bearing and axon-less horizontal cell subtypes are generated consecutively during chick retinal development from progenitors that are sensitive to follistatin2008In: BMC Developmental Biology, ISSN 1471-213X, E-ISSN 1471-213X, Vol. 8, 46- p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Horizontal cells are retinal interneurons that modulate the output from photoreceptors. A rich literature on the morphological classification and functional properties of HCs in different animals exists, however, the understanding of the events underlying their development is still limited. In most vertebrates including chicken, two main horizontal cell (HC) subtypes are identified based on the presence or absence of an axon.

    RESULTS:

    In this work we have molecularly characterized three HC subtypes based on Lim1, Isl1, GABA and TrkA, a classification that is consistent with three chick HC subtypes previously defined by morphology. The axon-bearing and axon-less HC subpopulations molecularly defined by Lim1 and Isl1, are born consecutively on embryonic day (E) 3-4 and E4-5, respectively, and exhibit temporally distinguishable periods of migration. Their relative numbers are not adjusted by apoptosis. A sharp decrease of high endogenous levels of the activin-inhibitor follistatin at E3 coincides with the appearance of the Lim1 positive cells. Extending the follistatin exposure of the HC retinal progenitor cells by injection of follistatin at E3 increased the number of both Lim1- and Isl1 positive HCs when analysed at E9.

    CONCLUSION:

    The results imply that the axon-bearing and axon-less HC subgroups are defined early and are generated consecutively from a retinal progenitor cell population that is sensitive to the inhibitory action of follistatin. The results are consistent with a model wherein added follistatin causes HC-generating progenitors to proliferate beyond the normal period of HC generation, thus producing extra HCs of both types that migrate to the HC layer.

  • 21.
    Edqvist, Per-Henrik D
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Niklasson, Mia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Vidal-Sanz, Manuel
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Platelet-derived growth factor over-expression in retinal progenitors results in abnormal retinal vessel formation2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 8, e42488- p.Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor (PDGF) plays an important role in development of the central nervous system, including the retina. Excessive PDGF signaling is associated with proliferative retinal disorders. We reported previously that transgenic mice in which PDGF-B was over-expressed under control of the nestin enhancer, nes/tk-PdgfB-lacZ, exhibited enhanced apoptosis in the developing corpus striatum. These animals display enlarged lateral ventricles after birth as well as behavioral aberrations as adults. Here, we report that in contrast to the relatively mild central nervous system phenotype, development of the retina is severely disturbed in nes/tk-PdgfB-lacZ mice.

    In transgenic retinas all nuclear layers were disorganized and photoreceptor segments failed to develop properly. Since astrocyte precursor cells did not populate the retina, retinal vascular progenitors could not form a network of vessels. With time, randomly distributed vessels resembling capillaries formed, but there were no large trunk vessels and the intraocular pressure was reduced. In addition, we observed a delayed regression of the hyaloid vasculature. The prolonged presence of this structure may contribute to the other abnormalities observed in the retina, including the defective lamination.

  • 22.
    Edqvist, Per-Henrik
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Medicinsk utvecklingsbiologi.
    Hallbook, Finn
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Medicinsk utvecklingsbiologi.
    Newborn horizontal cells migrate bi-directionally across the neuroepithelium during retinal development2004In: Development, Vol. 131, no 6, 1343-1251 p.Article in journal (Other (popular scientific, debate etc.))
  • 23.
    Edqvist, Per-Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Myers, Sarah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Early identification of retinal subtypes in the developing, pre-laminated chick retina using the transcription factors Prox1, Lim1, Ap2α, Pax6, Isl1, Isl2, Lim3 and Chx102006In: European journal of histochemistry, ISSN 1121-760X, E-ISSN 2038-8306, Vol. 50, no 2, 147-154 p.Article in journal (Refereed)
    Abstract [en]

    In this study, antibodies toward the transcription factors Prox1, Lim1, Ap2a, Pax6, Isl1, Isl2, Lim3 and Chx10 were used to identify and distinguish between developing cell types in the pre-laminated chick retina. The spatio-temporal expression patterns were analysed from embryonic day 3 (E3) to E9, thus covering a time-span from the onset of retinal cell-fate determination to when retinal laminas can be distinguished. Most transcription factors were found at early stages of development, enabling us to trace various precursor cell populations throughout the lamination process. With time, each transcription factor expression became restricted to distinct laminas or sub-laminas of the maturing retina. These early emerging patterns were compared and found to be consistent with those of the hatched chick retina, where the outer nuclear layer label for Lim3, Isl1 and Isl2. In the inner nuclear layer, horizontal cells labeled for Prox1, Lim1, Isl1, Ap2a and Pax6, bipolar cell labeled for Lim3, Isl1 and Chx10 and amacrine cells labeled for Ap2a, Isl1 and Pax6. The ganglion cell layer labeled for Isl1, Pax6 and Isl2. The immunolabeling patterns of Lim3 and Isl2 have not previously been described in detail.

  • 24.
    Fard, Shahrzad Shirazi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    All-Ericsson, Charlotta
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    The heterogenic final cell cycle of chicken retinal Lim1 horizontal cells is not regulated by the DNA damage response pathway2014In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 13, no 3, 408-417 p.Article in journal (Refereed)
    Abstract [en]

    Cells with aberrations in chromosomal ploidy are normally removed by apoptosis. However, aneuploid neurons have been shown to remain functional and active both in the cortex and in the retina. Lim1 horizontal progenitor cells in the chicken retina have a heterogenic final cell cycle, producing some cells that enter S-phase without proceeding into M-phase. The cells become heteroploid but do not undergo developmental cell death. This prompted us to investigate if the final cell cycle of these cells is under the regulation of an active DNA damage response. Our results show that the DNA damage response pathway, including gamma-H2AX and Rad51 foci, is not triggered during any phase of the different final cell cycles of horizontal progenitor cells. However, chemically inducing DNA adducts or double-strand breaks in Lim1 horizontal progenitor cells activated the DNA damage response pathway, showing that the cells are capable of a functional response to DNA damage. Moreover, manipulation of the DNA damage response pathway during the final cell cycle using inhibitors of ATM/ATR, Chk1/2, and p38MAPK, neither induced apoptosis nor mitosis in the Lim1 horizontal progenitor cells. We conclude that the DNA damage response pathway is functional in the Lim1 horizontal progenitor cells, but that it is not directly involved in the regulation of the final cell cycle that gives rise to the heteroploid horizontal cell population.

  • 25.
    Fard, Shahrzad Shirazi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Blixt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    The p53 co-activator Zac1 neither induces cell cycle arrest nor apoptosis in chicken Lim1 horizontal progenitor cells2015In: Cell Death Discovery, ISSN 2058-7716, Vol. 1, 15023Article in journal (Refereed)
    Abstract [en]

    Chicken horizontal progenitor cells are able to enter their final mitosis even in the presence of DNA damage despite having a functional p53-p21 system. This suggests that they are resistant to DNA damage and that the regulation of the final cell cycle of horizontal progenitor cells is independent of the p53-p21 system. The activity of p53 is regulated by positive and negative modulators, including the zinc finger containing transcription factor Zac1 (zinc finger protein that regulates apoptosis and cell cycle arrest). Zac1 interacts with and enhances the activity of p53, thereby inducing cell cycle arrest and apoptosis. In this work, we use a gain-of-function assay in which mouse Zac1 (mZac1) is overexpressed in chicken retinal progenitor cells to study the effect on the final cell cycle of horizontal progenitor cells. The results showed that overexpression of mZac1 induced expression of p21 in a p53-dependent way and arrested the cell cycle as well as triggered apoptosis in chicken non-horizontal retinal progenitor cells. The negative regulation of the cell cycle by mZac1 is consistent with its proposed role as a tumour-suppressor gene. However, the horizontal cells were not affected by mZac1 overexpression. They progressed into S- and late G2/M-phase despite overexpression of mZac1. The inability of mZac1 to arrest the cell cycle in horizontal progenitor cells support the notion that the horizontal cells are less sensitive to events that triggers the p53 system during their terminal and neurogenic cell cycle, compared with other retinal cells. These properties are associated with a cell that has a propensity to become neoplastic and thus with a cell that may develop retinoblastoma.

  • 26.
    Fard, Shahrzad Shirazi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Blixt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Whole Retinal Explants from Chicken Embryos for Electroporation and Chemical Reagent Treatments2015In: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, no 103, e53202Article in journal (Refereed)
    Abstract [en]

    The retina is a good model for the developing central nervous system. The large size of the eye and most importantly the accessibility for experimental manipulations in ovo/in vivo makes the chicken embryonic retina a versatile and very efficient experimental model. Although the chicken retina is easy to target in ovo by intraocular injections or electroporation, the effective and exact concentration of the reagents within the retina may be difficult to fully control. This may be due to variations of the exact injection site, leakage from the eye or uneven diffusion of the substances. Furthermore, the frequency of malformations and mortality after invasive manipulations such as electroporation is rather high. This protocol describes an ex ovo technique for culturing whole retinal explants from chicken embryos and provides a method for controlled exposure of the retina to reagents. The protocol describes how to dissect, experimentally manipulate, and culture whole retinal explants from chicken embryos. The explants can be cultured for approximately 24 hr and be subjected to different manipulations such as electroporation. The major advantages are that the experiment is not dependent on the survival of the embryo and that the concentration of the introduced reagent can be varied and controlled in order to determine and optimize the effective concentration. Furthermore, the technique is rapid, cheap and together with its high experimental success rate, it ensures reproducible results. It should be emphasized that it serves as an excellent complement to experiments performed in ovo.

  • 27.
    Fard, Shahrzad Shirazi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Jarrin, Miguel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Boije, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Fillon, Valerie
    All-Eriksson, Charlotta
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Heterogenic Final Cell Cycle by Chicken Retinal Lim1 Horizontal Progenitor Cells Leads to Heteroploid Cells with a Remaining Replicated Genome2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 3, e59133- p.Article in journal (Refereed)
    Abstract [en]

    Retinal progenitor cells undergo apical mitoses during the process of interkinetic nuclear migration and newly generated post-mitotic neurons migrate to their prospective retinal layer. Whereas this is valid for most types of retinal neurons, chicken horizontal cells are generated by delayed non-apical mitoses from dedicated progenitors. The regulation of such final cell cycle is not well understood and we have studied how Lim1 expressing horizontal progenitor cells (HPCs) exit the cell cycle. We have used markers for S-and G2/M-phase in combination with markers for cell cycle regulators Rb1, cyclin B1, cdc25C and p27Kip1 to characterise the final cell cycle of HPCs. The results show that Lim1+ HPCs are heterogenic with regards to when and during what phase they leave the final cell cycle. Not all horizontal cells were generated by a non-apical (basal) mitosis; instead, the HPCs exhibited three different behaviours during the final cell cycle. Thirty-five percent of the Lim1+ horizontal cells was estimated to be generated by non-apical mitoses. The other horizontal cells were either generated by an interkinetic nuclear migration with an apical mitosis or by a cell cycle with an S-phase that was not followed by any mitosis. Such cells remain with replicated DNA and may be regarded as somatic heteroploids. The observed heterogeneity of the final cell cycle was also seen in the expression of Rb1, cyclin B1, cdc25C and p27Kip1. Phosphorylated Rb1-Ser608 was restricted to the Lim1+ cells that entered S-phase while cyclin B1 and cdc25C were exclusively expressed in HPCs having a basal mitosis. Only HPCs that leave the cell cycle after an apical mitosis expressed p27Kip1. We speculate that the cell cycle heterogeneity with formation of heteroploid cells may present a cellular context that contributes to the suggested propensity of these cells to generate cancer when the retinoblastoma gene is mutated.

  • 28. Forrest, D
    et al.
    Hallböök, F
    Persson, H
    Vennström, B
    Distinct functions for thyroid hormone receptors alpha and beta in brain development indicated by differential expression of receptor genes.1991In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 10, no 2, 269-75 p.Article in journal (Refereed)
    Abstract [en]

    Thyroid hormones are essential for correct brain development, and since vertebrates express two thyroid hormone receptor genes (TR alpha and beta), we investigated TR gene expression during chick brain ontogenesis. In situ hybridization analyses showed that TR alpha mRNA was widely expressed from early embryonic stages, whereas TR beta was sharply induced after embryonic day 19 (E19), coinciding with the known hormone-sensitive period. Differential expression of TR mRNAs was striking in the cerebellum: TR beta mRNA was induced in white matter and granule cells after the migratory phase, suggesting a main TR beta function in late, hormone-dependent glial and neuronal maturation. In contrast, TR alpha mRNA was expressed in the earlier proliferating and migrating granule cells, and in the more mature granular and Purkinje cell layers after hatching, indicating a role for TR alpha in both immature and mature neural cells. Surprisingly, both TR genes were expressed in early cerebellar outgrowth at E9, before known hormone requirements, with TR beta mRNA restricted to the ventricular epithelium of the metencephalon and TR alpha expressed in migrating cells and the early granular layer. The results implicate TRs with distinct functions in the early embryonic brain as well as in the late phase of hormone requirement.

  • 29. Friedman, W J
    et al.
    Ibáñez, C F
    Hallböök, F
    Persson, H
    Cain, L D
    Dreyfus, C F
    Black, I B
    Differential actions of neurotrophins in the locus coeruleus and basal forebrain.1993In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 119, no 1, 72-8 p.Article in journal (Refereed)
    Abstract [en]

    The neurotrophin gene family, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4/NT-5, supports the survival of distinct peripheral neurons, however, actions upon central neurons are relatively undefined. In this study we have compared different neurotrophins in the regulation of neuronal survival and function using dissociated embryonic cell cultures from two brain regions, the basal forebrain (BF) and locus coeruleus (LC). In the BF, NGF increased choline acetyl transferase (ChAT) activity, but did not influence cholinergic cell survival. In contrast to NGF, BDNF, NT-3, and the novel neurotrophin, NT-4, all increased ChAT activity and cholinergic cell survival. We also examined embryonic LC neurons in culture. LC neurons are unresponsive to NGF. In contrast, NT-3 and NT-4 elicited significant increases in survival of noradrenergic LC neurons, the first demonstration of trophic effects in this critical brain region. Identification of factors supporting coeruleal and basal forebrain neuronal survival may provide insight into mechanisms mediating degeneration of these disparate structures in clinical disorders.

  • 30. Fritzsch, B
    et al.
    Hallböök, F
    A simple and reliable technique to combine oligonucleotide probe in situ hybridization with neuronal tract tracing in vertebrate embryos.1996In: Biotechnic & Histochemistry, ISSN 1052-0295, E-ISSN 1473-7760, Vol. 71, no 6, 289-94 p.Article in journal (Refereed)
    Abstract [en]

    We describe a simple and reliable combination of in situ hybridization with neuronal tracing. The technique uses recent advances in the field of neuronal tract tracing including fast diffusing, low molecular weight dextran amines and fade resistant fluorescent dyes, and combines them with in situ hybridization using a sensitive oligonucleotide probe. Using this technique we have investigated the mRNA encoding the trkB receptor for brain-derived neurotrophic factor in identified facial and vestibular afferent and efferent neurons. We found very low levels of trkB mRNA in facial efferent neurons, whereas in the vestibular afferent neurons, clear labeling for the trkB mRNA could be seen. This technique can be applied to the developing embryo to study topology of a variety of cellular markers with reference to neuronal population or fibers identified by their origin or target.

  • 31.
    Hallbook, Finn
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Med Utv Biol.
    Wilson, Karen
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Thorndyke, Mike
    Olinski, Robert
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Med Utv Biol.
    Formation and evolution of the chordate neurotrophin and Trk receptor genes.2006In: Brain Behav Evol, ISSN 0006-8977, Vol. 68, no 3, 133-44 p.Article in journal (Other scientific)
  • 32. Hallböök, F
    et al.
    Ayer-Lelièvre, C
    Ebendal, T
    Persson, H
    Expression of nerve growth factor receptor mRNA during early development of the chicken embryo: emphasis on cranial ganglia.1990In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 108, no 4, 693-704 p.Article in journal (Refereed)
    Abstract [en]

    In situ hybridization with beta-nerve growth factor receptor (NGF-R) oligonucleotide probes was used to study NGF-R mRNA expression in early chicken embryos. Sections through the region of the visceral arches showed high levels of NGF-R mRNA in mesenchyme of the visceral arches, neural tube and myotomes. Labelling was also seen over E3 primordium of the trigeminal ganglion (V) and in the placodal thickening of the petrosal (IX) and nodose (X) ganglionic primordia. In the E5 embryo, all cranial sensory ganglia (V, VII, VIII, IX, X) expressed NGF-R mRNA although at varying levels with higher levels in the ganglia of the Vth, IXth and Xth cranial nerves than in ganglia of the VIIth and the VIIIth nerves. Within ganglia of the Vth, IXth and Xth cranial nerves, levels of NGF-R mRNA were higher in regions containing placode-derived neurons, than in regions with neural-crest-derived neurons. The placode-derived nodose ganglion (X) expressed NGF-R mRNA at all stages of development. In the E15 embryo and later in development, two thirds of the large neuron-like cells expressed high levels of NGF-R mRNA. Our results show that expression of NGF-R mRNA, in peripheral neurons, is not restricted to cells of neural crest origin. We also show a transient expression of NGF-R mRNA early in development in a wide range of non-neuronal differentiating cells. The high level of NGF-R mRNA in early differentiating tissues suggest that the NGF-R plays a wider role during development than previously anticipated.

  • 33. Hallböök, F
    et al.
    Ibáñez, C F
    Persson, H
    Evolutionary studies of the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary.1991In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 6, no 5, 845-58 p.Article in journal (Refereed)
    Abstract [en]

    Evolutionary conservation of members of the NGF family in vertebrates was studied by DNA sequence analysis of PCR fragments for NGF, BDNF, and NT-3 from human, rat, chicken, viper, Xenopus, salmon, and ray. The results showed that the three factors are highly conserved from fishes to mammals. Phylogenetic trees reflecting the evolution and speciation of the members of the NGF family were constructed. In addition, the gene for a fourth member of the family, neurotrophin-4 (NT-4), was isolated from Xenopus and viper. The NT-4 gene encodes a precursor protein of 236 amino acids, which is processed into a 123 amino acid mature NT-4 protein with 50%-60% amino acid identity to NGF, BDNF, and NT-3. The NT-4 protein was shown to interact with the low affinity NGF receptor and elicited neurite outgrowth from explanted dorsal root ganglia with no and lower activity in sympathetic and nodose ganglia, respectively. Northern blot analysis of different tissues from Xenopus showed NT-4 mRNA only in ovary, where it was present at levels over 100-fold higher than those of NGF mRNA in heart.

  • 34. Hallböök, F
    et al.
    Persson, H
    Barbany, G
    Ebendal, T
    Development and regional expression of chicken neuroleukin (glucose-6-phosphate isomerase) messenger RNA.1989In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 23, no 2, 142-51 p.Article in journal (Refereed)
    Abstract [en]

    Neuroleukin (NLK) is a protein identical with the glycolytic enzyme glucose-6-phosphate isomerase (GPI) that has been reported to support the survival of a subpopulation of neurons in embryonic dorsal root ganglia and spinal cord neurons in culture. In this report we have studied the developmental expression of NLK mRNA in the chick embryo in order to evaluate its possible role as a neurotrophic factor. The chicken gene encoding NLK was isolated by cross-hybridization to a mouse NLK cDNA clone. A DNA fragment from the chicken NLK gene with a 90% nucleotide sequence homology to mouse NLK cDNA encoding amino acids 310-355 was then used as a hybridization probe in a series of RNA-blots. In the entire embryo NLK mRNA was found already at embryonic day 3.5 (E3.5) and the level of expression was significantly decreased between E3.5 and hatching. Roughly similar levels of NLK mRNA were found in all tissues of the E8 embryo analyzed with the exception of the brain, which contained only low levels. When the developmental expression was analyzed in different tissues separately, NLK mRNA expression was found to decrease during development in the heart and bursa of Fabricius, whereas the level of mRNA in the brain showed a large increase shortly after hatching. The spinal cord and the pectoral and femoral muscles all showed high levels of NLK mRNA throughout development. In the adult chick, the highest levels of NLK mRNA were found in the muscle, brain, and kidney, where the NLK mRNA was estimated to account for approximately 0.1% of the total mRNA in these tissues. A widespread expression of NLK mRNA was observed in the adult brain with approximately similar levels in all brain regions tested. Similar results were also obtained when NLK mRNA expression was analyzed in adult rats. Our results show that developmental expression of the NLK gene is independently regulated in different tissues. The widespread and abundant expression of both the avian and rodent NLK gene is in accordance with its newly discovered identity as a glycolytic enzyme. Consequently, the developmental and adult pattern of NLK mRNA expression does not favour a specific trophic role for this protein in accordance with other known neurotrophic factors.

  • 35.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Evolution of the vertebrate neurotrophin and Trk receptor gene families1999In: Current Opinion in Neurobiology, ISSN 0959-4388, E-ISSN 1873-6882, Vol. 9, no 5, 616-621 p.Article in journal (Refereed)
    Abstract [en]

    Studies of neurotrophins and Trk receptors in jawless fish have shed light on the course of events underlying the formation of these gene families. They evolved early in vertebrate history during major gene duplication events, before the appearance of cartilaginous fish. The existence of multiple genes has permitted the diversification of neurotrophin and Trk receptor expression, and thereby enabling the acquisition of specific functions in selective neuronal populations.

  • 36.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Evolution of the vertebrate neurotrophin and Trk receptor gene families1999In: Current Opinion in Neurobiology, ISSN 0959-4388, E-ISSN 1873-6882, Vol. 9, no 5, 616-621 p.Article in journal (Refereed)
    Abstract [en]

    Studies of neurotrophins and Trk receptors in jawless fish have shed light on the course of events underlying the formation of these gene families. They evolved early in vertebrate history during major gene duplication events, before the appearance of cartilaginous fish. The existence of multiple genes has permitted the diversification of neurotrophin and Trk receptor expression, and thereby enabling the acquisition of specific functions in selective neuronal populations.

  • 37.
    Hallböök, Finn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Bäckström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Ebendal, Ted
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Carri, Nestor G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Expression of neurotrophins and trk receptors in the avian retina1996In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 364, no 4, 664-676 p.Article in journal (Refereed)
    Abstract [en]

    Using the RNase protection assay, we have found that nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) are expressed in the avian retina during development. The expression peaks around embryonic days 12-15, with decreasing levels at later stages of development. Abundant levels of NGF and BDNF but low levels of NT-3 mRNA were found in the adult retina. We also found that light/darkness regulated the levels of NGF and BDNF mRNAs but not the levels of NT-3 mRNA in the 5-day-old chicken retina. It was demonstrated that NGF and BDNF mRNA levels were up-regulated by light exposure. The cellular localization of mRNA expression for the neurotrophins and neurotrophin receptors TrkA, TrkB, and TrkC in the retina was studied using in situ hybridization. The patterns of NGF and trkA mRNA expression were very similar and were localized to the external part of the inner nuclear layer on the border with the outer plexiform layer and corresponded to the localization of horizontal cells. NT-3 labeling was also found over the external part of the inner nuclear layer, whereas trkC mRNA was found over all layers in the retina. BDNF labeling was found over all layers in the retina, whereas TrkB labeling was intense over cells in the ganglion cell layer, which is in agreement with the response of ganglion cells to BDNF stimulation. Functional neurotrophin receptors were suggested by the response of retinal explants to neurotrophin stimulation. These data indicate that the neurotrophins play local roles in the retina that involve interactions between specific neuronal populations, which were identified by the localization of the Trk receptor expression. The data also suggest that NGF and BDNF expression is regulated by normal neuron usage in the retina.

  • 38.
    Hallböök, Finn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Bäckström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Kylberg, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Williams, Reg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Ebendal, Ted
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Neurotrophins and their receptors in chicken neuronal development1995In: International Journal of Developmental Biology, ISSN 0214-6282, E-ISSN 1696-3547, Vol. 39, no 5, 855-868 p.Article in journal (Refereed)
    Abstract [en]

    A review on current studies of chicken neurotrophins and their receptors is given. Chicken NGF, BDNF and NT-3 have been cloned and sequences have been used to synthesize oligonucleotides for specific localization of expression during development. Also, chicken TrkA, TrkB and TrkC have been cloned, sequenced and studied by in situ hybridization. Recombinant NT-3 was applied to chicken ganglia at different developmental stages to examine acquirement of responsiveness to NT-3 compared to NGF. Phylogenetic analyses of the chicken neurotrophins and Trk receptors were carried out based on parsimony. Finally, some data on apoptosis in chicken embryo sympathetic ganglia are presented.

  • 39.
    Hallböök, Finn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Catsicas, M
    Staple, J K
    Grenningloh, G
    Catsicas, S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Gene functional analysis in nervous system2000In: Methods in Enzymology, ISSN 0076-6879, E-ISSN 1557-7988, Vol. 314, 148-167 p.Article in journal (Refereed)
  • 40.
    Hallböök, Finn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Catsicas, M
    Staple, JK
    Grenningloh, G
    Catsicas, S
    Gene functional analysis in the nervous system2000In: Methods in Enzymology, ISSN 0076-6879, E-ISSN 1557-7988, Vol. 314, 148-167 p.Article in journal (Refereed)
  • 41.
    Hallböök, Finn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Ebendal, Ted
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Zoology.
    Persson, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Production and characterization of biologically active recombinant beta nerve growth factor1988In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 8, no 1, 452-456 p.Article in journal (Refereed)
    Abstract [en]

    DNA fragments encoding either rat or chicken beta nerve growth factor (NGF) were inserted in the expression vector p91023(B) for transient expression in COS cells. The two NGF constructs produced RNA transcripts and proteins of the predicted sizes. Conditioned media from the transfected cells stimulated neurite outgrowth from cultured chicken embryo sympathetic ganglia. The results show that the rat or chicken NGF gene can direct the synthesis of a biologically active NGF protein after transfection of COS cells.

  • 42.
    Hallböök, Finn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Fritzsch, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Distribution of BDNF and trkB mRNA in the otic region of 3.5 and 4.5 day chick embryos as revealed with a combination of in situ hybridization and tract tracing1997In: International Journal of Developmental Biology, ISSN 0214-6282, E-ISSN 1696-3547, Vol. 41, no 5, 725-732 p.Article in journal (Refereed)
    Abstract [en]

    We have used a recently developed technique which combines fluorescent tract tracing and in situ hybridization to study co-localization of neurotrophin mRNA and neurotrophin receptor mRNA expression simultaneously with the pattern of innervation in the developing chick ear. Efferent and afferent fibersfrom the VII/VIIIth cranial nerves were retrogradely and anterogradely filled with Dextran amines conjugated to Texas red and the brain stem was incubated for 2 hours in tissue culture medium. The tissue was subsequently fixed, sectioned frozen, mounted and subjected to in situ hybridization analysis using probes for brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor, trkB. The results show that afferent and efferent fibers to the ear innervate areas of the developing otocyst which express BDNF mRNA. We also found that neurons in the stato-acoustic ganglion express high levels of trkB mRNA whereas the subset of facial motor neurons that is efferent to the ear only had no or very low levels of trkB mRNA. From our results we conclude that chicken otic efferent fibers preferentially project to areas with BDNF mRNA expression. The very low levels of trkB mRNA in these motor neurons compared to afferent neurons innervating the same region suggest that other factors, perhaps co-expressed with BDNF, may support efferents. A possible involvement of afferents in guiding efferents to specific areas of the ear is suggested.

  • 43.
    Hallböök, Finn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Lundin, L-G
    Evolution of the neurotrophins and their receptors1999Book (Other academic)
  • 44.
    Hallböök, Finn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Lundin, Lars-Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Lampetra fluviatilis neurotrophin homolog, descendant of a neurotrophin ancestor, discloses the early molecular evolution of neurotrophins in the vertebrate subphylum1998In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 18, no 21, 8700-8711 p.Article in journal (Refereed)
    Abstract [en]

    We have isolated a neurotrophin from the lamprey that permitted us to perform a phylogenetic analysis of the neurotrophin gene family that dates back more than 460 million years to the early vertebrate ancestors. The results show that the neurotrophin gene family was originally formed by two subsequent duplications. The duplication that formed nerve growth factor, neurotrophin-3, brain-derived neurotrophic factor, and neurotrophin-4/5 occurred after the split of lampreys but before the split of cartilaginous fish from the main vertebrate lineage. Compilation of chromosomal gene maps around the neurotrophins shows that they are located in paralogous regions, suggesting that the genes were formed at major duplication events possibly by complete genome doubling. Analysis of two isolated Trk receptor sequences shows similar results as for the lamprey neurotrophin. Multiple neurotrophin and Trk genes, including neurotrophin-6 and -7, have been found in bony fish, and we suggest that the extra genes were formed by an additional duplication in the bony fish lineage. Analysis of lamprey Trk mRNA expression in the adult brain shows that the genes are expressed in all regions analyzed so far. Together, the results suggest that the duplications of ancestral neurotrophin and Trk genes at an early vertebrate stage have permitted evolution to bring about differential neurotrophin and Trk expression, thereby allowing the formation of specific functions in selective neuronal populations.

  • 45.
    Hallböök, Finn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Sahlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Catsicas, S
    Characterization and evaluation of antisense oligonucleotides: inhibition of NGF synthesis in transfected COS cells1997In: Antisense and Nucleic Acid Drug Development, ISSN 1087-2906, E-ISSN 2168-6599, Vol. 7, no 2, 89-100 p.Article in journal (Refereed)
    Abstract [en]

    We present a system for the assessment of the inhibiting capacity of antisense oligonucleotides. The aim of this study was to identify an oligonucleotide that can inhibit chicken nerve growth factor (NGF) synthesis. Five antisense chicken NGF phosphorothioate oligonucleotides, AS1–5, were designed and were tested for their capacity to inhibit NGF expression in COS cells. COS cells that transiently expressed chicken NGF were treated with the oligonucleotides, and NGF expression was analyzed using a bioassay and Western blotting for NGF protein. Two oligonucleotides, AS 1 and AS 5, were more capable than the others of inhibiting expression compared with nonsense oligonucleotide, and they targeted the translational initiation and stop sites. The chicken NGF is expressed at a high level from an adenovirus major late promoter, and AS 1 was capable of inhibiting more than 80% of the NGF expression as determined using the bioassay and Western blotting. Expression of another member of the NGF gene family, neurotrophin-4, was not affected by treatment of the antisense oligonucleotides. A 10-fold lower concentration of the AS 1 oligonucleotide could be used to inhibit NGF synthesis if the cellular uptake was facilitated using lipofectin compared with addition of oligonucleotide directly to the culture medium. The amount of oligonucleotide taken up by the cells was similar in the lipofectin-treated cells as in the cells treated by a 10-fold higher concentration of medium-supplemented nucleotide. This system based on COS cells can facilitate evaluation of the capacity of inhibiting antisense oligonucleotides, particularly targeting those genes in which endogenous products are present in low levels and are difficult to analyze.

  • 46.
    Hallböök, Finn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Wilson, Karen
    Thorndyke, Mike
    Olinski, Robert Piotr
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Formation and evolution of the chordate neurotrophin and Trk receptor genes2006In: Brain, behavior, and evolution, ISSN 0006-8977, E-ISSN 1421-9743, Vol. 68, no 3, 133-144 p.Article in journal (Refereed)
    Abstract [en]

    Neurotrophins are structurally related neurotrophic polypeptide factors that regulate neuronal differentiation and are essential for neuronal survival, neurite growth and plasticity. It has until very recently been thought that the neurotrophin system appeared with the vertebrate species, but identification of a cephalochordate neurotrophin receptor (Trk), and more recently neurotrophin sequences in several genomes of deuterostome invertebrates, show that the system already existed at the stem of the deuterostome group. Comparative genomics supports the hypothesis that two whole genome duplications produced many of the vertebrate gene families, among those the neurotrophin and Trk families. It remains to be proven to what extent the whole genome duplications have driven macroevolutionary change, but it appears certain that the formation of the multi-gene copy neurotrophin and Trk receptor families at the stem of vertebrates has provided a foundation from which the various functions and pleiotropic effects produced by each of the four extant neurotrophins have evolved.

  • 47.
    Harun-Or-Rashid, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Diaz-DelCastillo, Marta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Galindo-Romero, Caridad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Alpha2-Adrenergic-Agonist Brimonidine Stimulates Negative Feedback and Attenuates Injury-Induced Phospho-ERK and Dedifferentiation of Chicken Müller Cells2015In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 56, no 10, 5933-5945 p.Article in journal (Refereed)
    Abstract [en]

    Purpose:

    Retinal injury induces Müller cell dedifferentiation by activating extracellular signal-regulated kinase (ERK) signaling. Stimulation of α2-adrenergic receptors protects against injury but also activates ERK in Müller cells. The purpose of this work was to study the effect of α2-adrenergic signaling on injury-induced ERK and Müller cell dedifferentiation. We tested the hypothesis that α2-stimulation triggers negative feedback regulation of the injury-induced ERK pathway that attenuates Müller cell dedifferentiation.

    Methods:

    Chicken retina injured by N-methyl-D-aspartate and cultured primary Müller cells were stimulated by the α2-adrenergic agonist brimonidine. Immunostaining, quantitative RT-PCR, and Western blot techniques in combination with receptor blockers were used for analysis of the cellular responses.

    Results:

    Alpha2-adrenergic receptor stimulation attenuated injury-induced ERK activation and dedifferentiation of Müller cells as seen by decreased phospho-ERK, expression of transitin, and retinal progenitor cell genes. The attenuation was concomitant with a synergistic upregulation of several negative ERK-signal feedback regulators including ERK-phosphatases, Raf1-, and growth factor receptor–binding proteins. The results were also seen in cultures of primary Müller cells.

    Conclusions:

    Alpha2-adrenergic signaling on Müller cells elicits an intracellular attenuation of the injury response that comprises negative ERK-signaling feedback leading to attenuated Müller cell dedifferentiation. The implications of this study are that adrenergic stress signals may directly modulate glial function in retina and that α2-adrenergic receptor pharmacology may be used to control glial injury response.

  • 48.
    Harun-Or-Rashid, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Konjusha, Dardan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Galindo-Romero, Caridad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Univ Murcia, Fac Med, Dept Oftalmol, Murcia, Spain.;Inst Murciano Invest Biosanitaria Virgen Arrixaca, Murcia, Spain..
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Endothelin B Receptors on Primary Chicken Müller Cells and the Human MIO-M1 Müller Cell Line Activate ERK Signaling via Transactivation of Epidermal Growth Factor Receptors2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 12, e0167778Article in journal (Refereed)
    Abstract [en]

    Injury to the eye or retina triggers Muller cells, the major glia cell of the retina, to dedifferentiate and proliferate. In some species they attain retinal progenitor properties and have the capacity to generate new neurons. The epidermal growth factor receptor (EGFR) system and extracellular signal-regulated kinase (ERK) signaling are key regulators of these processes in Muller cells. The extracellular signals that modulate and control these processes are not fully understood. In this work we studied whether endothelin receptor signaling can activate EGFR and ERK signaling in Muller cells. Endothelin expression is robustly upregulated at retinal injury and endothelin receptors have been shown to transactivate EGFRs in other cell types. We analyzed the endothelin signaling system in chicken retina and cultured primary chicken Muller cells as well as the human Muller cell line MIO-M1. The Muller cells were stimulated with receptor agonists and treated with specific blockers to key enzymes in the signaling pathway or with siRNAs. We focused on endothelin receptor mediated transactivation of EGFRs by using western blot analysis, quantitative reverse transcriptase PCR and immunocytochemistry. The results showed that chicken Muller cells and the human Muller cell line MIO-M1 express endothelin receptor B. Stimulation by the endothelin receptor B agonist IRL1620 triggered phosphorylation of ERK1/2 and autophosphorylation of (Y1173) EGFR. The effects could be blocked by Src-kinase inhibitors (PP1, PP2), EGFR-inhibitor (AG1478), EGFR-siRNA and by inhibitors to extracellular matrix metalloproteinases (GM6001), consistent with a Src-kinase mediated endothelin receptor response that engage ligand-dependent and ligand-independent EGFR activation. Our data suggest a mechanism for how injury-induced endothelins, produced in the retina, may modulate the Muller cell responses by Src-mediated transactivation of EGFRs. The data give support to a view in which endothelins among several other functions, serve as an injury-signal that regulate the gliotic response of Muller cells.

  • 49.
    Harun-Or-Rashid, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Lindqvist, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Transactivation of EGF Receptors in Chicken Muller Cells by α2A-Adrenergic Receptors Stimulated by Brimonidine2014In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 55, no 6, 3385-3394 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: α2-Adrenergic receptor agonists are used in glaucoma treatment and have been shown to have some neuroprotective effects. We performed this study to test the hypothesis that epidermal growth factor receptors on chicken Müller cells are transactivated by α2-adrenergic receptors and we focused on the extracellular signal-activated kinases 1/2 (ERK) pathway. Methods: Embryonic chicken retina and cultures of primary Müller cells were stimulated by α2-adrenergic receptor agonist brimonidine. Immunostaining, qRT-PCR and western blot techniques in combination with Src-, epidermal growth factor receptor kinase-, and matrix metalloproteinase inhibitors were used for analysis of the cellular responses. Results: Our results showed that Müller cells express α2A-adrenergic receptors in vivo and in vitro and that brimonidine triggered a robust and transient phosphorylation of ERK1/2. This ERK-response was Src-kinase dependent, associated with tyrosine phosphorylation of epidermal growth factor receptors (phospho-Y1068, Y1173) and was mediated by matrix metalloproteinase-activity on the Müller cells. Conclusions: Müller cells express the α2A-adrenergic receptor and brimonidine triggers both Src-kinase- and matrix metalloproteinase-mediated autocrine ligand-dependent activation of epidermal growth factor receptors on Müller cell. This response is consistent with transactivation of epidermal growth factor receptors by stimulation of α2-adrenergic receptors.

  • 50.
    Hellström, Anders R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Watt, Brenda
    Fard, Shahrzad Shirazi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Tenza, Daniele
    Mannström, Paula
    Narfström, Kristina
    Ekesten, Björn
    Ito, Shosuke
    Wakamatsu, Kazumasa
    Larsson, Jimmy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Ulfendahl, Mats
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Raposo, Graca
    Kerje, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Marks, Michael S.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Inactivation of Pmel Alters Melanosome Shape But Has Only a Subtle Effect on Visible Pigmentation2011In: PLoS Genetics, ISSN 1553-7390, Vol. 7, no 9, e1002285- p.Article in journal (Refereed)
    Abstract [en]

    PMEL is an amyloidogenic protein that appears to be exclusively expressed in pigment cells and forms intralumenal fibrils within early stage melanosomes upon which eumelanins deposit in later stages. PMEL is well conserved among vertebrates, and allelic variants in several species are associated with reduced levels of eumelanin in epidermal tissues. However, in most of these cases it is not clear whether the allelic variants reflect gain-of-function or loss-of-function, and no complete PMEL loss-of-function has been reported in a mammal. Here, we have created a mouse line in which the Pmel gene has been inactivated (Pmel(-/-)). These mice are fully viable, fertile, and display no obvious developmental defects. Melanosomes within Pmel(-/-) melanocytes are spherical in contrast to the oblong shape present in wild-type animals. This feature was documented in primary cultures of skin-derived melanocytes as well as in retinal pigment epithelium cells and in uveal melanocytes. Inactivation of Pmel has only a mild effect on the coat color phenotype in four different genetic backgrounds, with the clearest effect in mice also carrying the brown/Tyrp1 mutation. This phenotype, which is similar to that observed with the spontaneous silver mutation in mice, strongly suggests that other previously described alleles in vertebrates with more striking effects on pigmentation are dominant-negative mutations. Despite a mild effect on visible pigmentation, inactivation of Pmel led to a substantial reduction in eumelanin content in hair, which demonstrates that PMEL has a critical role for maintaining efficient epidermal pigmentation.

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