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Hallböök, Finn
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Publications (10 of 95) Show all publications
Stenfelt, S., Blixt, M. K. E., All-Ericsson, C., Hallböök, F. & Boije, H. (2017). Heterogeneity in retinoblastoma: a tale of molecules and models. CLINICAL AND TRANSLATIONAL MEDICINE, 6, Article ID 42.
Open this publication in new window or tab >>Heterogeneity in retinoblastoma: a tale of molecules and models
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2017 (English)In: CLINICAL AND TRANSLATIONAL MEDICINE, ISSN 2001-1326, Vol. 6, article id 42Article, review/survey (Refereed) Published
Abstract [en]

Retinoblastoma, an intraocular pediatric cancer, develops in the embryonic retina following biallelic loss of RB1. However, there is a wide range of genetic and epigenetic changes that can affect RB1 resulting in different clinical outcomes. In addition, other transformations, such as MYCN amplification, generate particularly aggressive tumors, which may or may not be RB1 independent. Recognizing the cellular characteristics required for tumor development, by identifying the elusive cell-of-origin for retinoblastoma, would help us understand the development of these tumors. In this review we summarize the heterogeneity reported in retinoblastoma on a molecular, cellular and tissue level. We also discuss the challenging heterogeneity in current retinoblastoma models and suggest future platforms that could contribute to improved understanding of tumor initiation, progression and metastasis in retinoblastoma, which may ultimately lead to more patient-specific treatments.

Place, publisher, year, edition, pages
BIOMED CENTRAL LTD, 2017
Keyword
Cancer, Cell-of-origin, Genetics, Horizontal cells, MYCN, Photoreceptors, OTX2, RB1
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-346610 (URN)10.1186/s40169-017-0173-2 (DOI)000414747600001 ()
Available from: 2018-03-22 Created: 2018-03-22 Last updated: 2018-03-22Bibliographically approved
Thalmann, D. S., Ring, H., Sundström, E., Cao, X., Larsson, M., Kerje, S., . . . Andersson, L. (2017). The evolution of Sex-linked barring alleles in chickens involves both regulatory and coding changes in CDKN2A. PLoS Genetics, 13(4), Article ID e1006665.
Open this publication in new window or tab >>The evolution of Sex-linked barring alleles in chickens involves both regulatory and coding changes in CDKN2A
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2017 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 4, article id e1006665Article in journal (Refereed) Published
Abstract [en]

Sex-linked barring is a fascinating plumage pattern in chickens recently shown to be associated with two non-coding and two missense mutations affecting the ARF transcript at the CDKN2A tumor suppressor locus. It however remained a mystery whether all four mutations are indeed causative and how they contribute to the barring phenotype. Here, we show that Sex-linked barring is genetically heterogeneous, and that the mutations form three functionally different variant alleles. The B0 allele carries only the two non-coding changes and is associated with the most dilute barring pattern, whereas the B1 and B2 alleles carry both the two non-coding changes and one each of the two missense mutations causing the Sex-linked barring and Sex-linked dilution phenotypes, respectively. The data are consistent with evolution of alleles where the non-coding changes occurred first followed by the two missense mutations that resulted in a phenotype more appealing to humans. We show that one or both of the non-coding changes are cis-regulatory mutations causing a higher CDKN2A expression, whereas the missense mutations reduce the ability of ARF to interact with MDM2. Caspase assays for all genotypes revealed no apoptotic events and our results are consistent with a recent study indicating that the loss of melanocyte progenitors in Sex-linked barring in chicken is caused by premature differentiation and not apoptosis. Our results show that CDKN2A is a major locus driving the differentiation of avian melanocytes in a temporal and spatial manner.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2017
Keyword
ARF TUMOR-SUPPRESSOR; GENE-EXPRESSION; LOCUS; MUTATIONS; INK4A/ARF; MELANOMA; GENOME; SENESCENCE; NICHE; CELLS
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-327066 (URN)10.1371/journal.pgen.1006665 (DOI)000402549200008 ()
Available from: 2017-08-01 Created: 2017-08-01 Last updated: 2018-01-03Bibliographically approved
Blixt, M. & Hallböök, F. (2016). A regulatory sequence from the retinoid X receptor gamma gene directs expression to horizontal cells and photoreceptors in the embryonic chicken retina. Molecular Vision, 22, 1405-1420
Open this publication in new window or tab >>A regulatory sequence from the retinoid X receptor gamma gene directs expression to horizontal cells and photoreceptors in the embryonic chicken retina
2016 (English)In: Molecular Vision, ISSN 1090-0535, E-ISSN 1090-0535, Vol. 22, p. 1405-1420Article in journal (Refereed) Published
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.

National Category
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-313804 (URN)000393909400001 ()28003731 (PubMedID)
Funder
Swedish Research Council, MH521.2013.3346Swedish Childhood Cancer Foundation
Available from: 2017-01-24 Created: 2017-01-24 Last updated: 2017-11-29Bibliographically approved
Harun-Or-Rashid, M., Konjusha, D., Galindo-Romero, C. & Hallböök, F. (2016). 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 Receptors. PLoS ONE, 11(12), Article ID e0167778.
Open this publication in new window or tab >>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 Receptors
2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 12, article id e0167778Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-312630 (URN)10.1371/journal.pone.0167778 (DOI)000389580900045 ()27930693 (PubMedID)
Funder
Swedish Research Council, M 12187
Available from: 2017-01-26 Created: 2017-01-12 Last updated: 2017-11-29Bibliographically approved
Boije, H., Fard, S. S., Edqvist, P.-H. & Hallböök, F. (2016). Horizontal Cells, the Odd Ones Out in the Retina, Give Insights into Development and Disease. Frontiers in Neuroanatomy, 10, Article ID 77.
Open this publication in new window or tab >>Horizontal Cells, the Odd Ones Out in the Retina, Give Insights into Development and Disease
2016 (English)In: Frontiers in Neuroanatomy, ISSN 1662-5129, E-ISSN 1662-5129, Vol. 10, article id 77Article, review/survey (Refereed) Published
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.

Keyword
cell fate, cell cycle regulation, chicken, development, DNA damage, neuronal subtype, retinoblastoma, zebrafish
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-301132 (URN)10.3389/fnana.2016.00077 (DOI)000379879400001 ()
Funder
Swedish Research Council
Available from: 2016-08-22 Created: 2016-08-18 Last updated: 2017-11-28Bibliographically approved
Blixt, M. & Hallböök, F. (2016). Lineage tracing of horizontal and photoreceptor cells in the embryonic chicken retina. Paper presented at Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), MAY 01-05, 2016, Seattle, WA. Investigative Ophthalmology and Visual Science, 57(12)
Open this publication in new window or tab >>Lineage tracing of horizontal and photoreceptor cells in the embryonic chicken retina
2016 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 57, no 12Article in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2016
National Category
Ophthalmology
Identifiers
urn:nbn:se:uu:diva-321043 (URN)000394174004160 ()
Conference
Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), MAY 01-05, 2016, Seattle, WA
Available from: 2017-04-28 Created: 2017-04-28 Last updated: 2017-04-28Bibliographically approved
Dorshorst, B., Harun-Or-Rashid, M., Bagherpoor, A. J., Rubin, C.-J., Ashwell, C., Gourichon, D., . . . Andersson, L. (2015). A Genomic Duplication is Associated with Ectopic Eomesodermin Expression in the Embryonic Chicken Comb and Two Duplex-comb Phenotypes. PLOS Genetics, 11(3), Article ID e1004947.
Open this publication in new window or tab >>A Genomic Duplication is Associated with Ectopic Eomesodermin Expression in the Embryonic Chicken Comb and Two Duplex-comb Phenotypes
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2015 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 3, article id e1004947Article in journal (Refereed) Published
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.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-248610 (URN)10.1371/journal.pgen.1004947 (DOI)000352197100002 ()25789773 (PubMedID)
Available from: 2015-04-02 Created: 2015-04-02 Last updated: 2018-01-11Bibliographically approved
Blixt, M. K. E., Shirazi Fard, S., All-Ericsson, C. & Hallböök, F. (2015). Adding another piece to the retinoblastoma puzzle. Cell Death and Disease, 6, Article ID e1957.
Open this publication in new window or tab >>Adding another piece to the retinoblastoma puzzle
2015 (English)In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 6, article id e1957Article in journal, Editorial material (Refereed) Published
Place, publisher, year, edition, pages
Nature Publishing Group, 2015
National Category
Medical and Health Sciences Cell and Molecular Biology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-279036 (URN)10.1038/cddis.2015.317 (DOI)000367150100040 ()26512965 (PubMedID)
Available from: 2016-02-28 Created: 2016-02-28 Last updated: 2018-01-10Bibliographically approved
Harun-Or-Rashid, M., Diaz-DelCastillo, M., Galindo-Romero, C. & Hallböök, F. (2015). Alpha2-Adrenergic-Agonist Brimonidine Stimulates Negative Feedback and Attenuates Injury-Induced Phospho-ERK and Dedifferentiation of Chicken Müller Cells. Investigative Ophthalmology and Visual Science, 56(10), 5933-5945
Open this publication in new window or tab >>Alpha2-Adrenergic-Agonist Brimonidine Stimulates Negative Feedback and Attenuates Injury-Induced Phospho-ERK and Dedifferentiation of Chicken Müller Cells
2015 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 56, no 10, p. 5933-5945Article in journal (Refereed) Published
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.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-262700 (URN)10.1167/iovs.15-16816 (DOI)000368426300032 ()
Funder
Swedish Research Council, M 12187
Available from: 2015-09-18 Created: 2015-09-18 Last updated: 2018-01-11Bibliographically approved
Fard, S. S., Blixt, M. & Hallböök, F. (2015). The p53 co-activator Zac1 neither induces cell cycle arrest nor apoptosis in chicken Lim1 horizontal progenitor cells. Cell Death Discovery, 1, Article ID 15023.
Open this publication in new window or tab >>The p53 co-activator Zac1 neither induces cell cycle arrest nor apoptosis in chicken Lim1 horizontal progenitor cells
2015 (English)In: Cell Death Discovery, ISSN 2058-7716, Vol. 1, article id 15023Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2015
National Category
Neurology Developmental Biology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-279034 (URN)10.1038/cddiscovery.2015.23 (DOI)
Available from: 2016-02-28 Created: 2016-02-28 Last updated: 2017-02-17Bibliographically approved
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