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Ring, Henrik
Publications (10 of 10) Show all publications
Blixt, M. K. E., Konjusha, D., Ring, H. & Hallböök, F. (2018). Zinc finger gene nolz1 regulates the formation of retinal progenitor cells and suppresses the Lim3/Lhx3 phenotype of retinal bipolar cells in chicken retina. Developmental Dynamics, 247(4), 630-641
Open this publication in new window or tab >>Zinc finger gene nolz1 regulates the formation of retinal progenitor cells and suppresses the Lim3/Lhx3 phenotype of retinal bipolar cells in chicken retina
2018 (English)In: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 247, no 4, p. 630-641Article in journal (Refereed) Published
Abstract [en]

Background: The zinc-finger transcription factor Nolz1 regulates spinal cord neuron development by interacting with the transcription factors Isl1, Lim1, and Lim3, which are also important for photoreceptors, horizontal and bipolar cells during retinal development. We, therefore, studied Nolz1 during retinal development.

Results: Nolz1 expression was seen in two waves during development: one early (peak at embryonic day 3-4.5) in retinal progenitors and one late (embryonic day 8) in newly differentiated cells in the inner nuclear layer. Overexpression and knockdown showed that Nolz1 decreases proliferation and stimulates cell cycle withdrawal in retinal progenitors with effects on the generation of retinal ganglion cells, photoreceptors, and horizontal cells without triggering apoptosis. Overexpression of Nolz1 gave more p27 positive cells. Sustained overexpression of Nolz1 in the retina gave fewer Lim3/Lhx3 bipolar cells.

Conclusions: We conclude that Nolz1 has multiple functions during development and suggest a mechanism in which Nolz1 initially regulates the proliferation state of the retinal progenitor cells and then acts as a repressor that suppresses the Lim3/Lhx3 bipolar cell phenotype at the time of bipolar cell differentiation.

Place, publisher, year, edition, pages
WILEY, 2018
Keywords
chicken embryo, differentiation, horizontal cells, in ovo electroporation, Isl1, Lim1, morpholino, p27, piggyback, photoreceptors, repressor
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-350726 (URN)10.1002/dvdy.24607 (DOI)000427563200005 ()29139167 (PubMedID)
Funder
Swedish Research Council, MH521.2013.3346]Swedish Childhood Cancer Foundation, PR20150122]
Available from: 2018-05-17 Created: 2018-05-17 Last updated: 2018-05-17Bibliographically 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
Keywords
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
Boije, H., Ring, H., Fard, S. S., Grundberg, I., Nilsson, M. & Hallbook, F. (2013). Alternative Splicing of the Chromodomain Protein Morf4l1 Pre-mRNA Has Implications on Cell Differentiation in the Developing Chicken Retina. Journal of Molecular Neuroscience, 51(2), 615-628
Open this publication in new window or tab >>Alternative Splicing of the Chromodomain Protein Morf4l1 Pre-mRNA Has Implications on Cell Differentiation in the Developing Chicken Retina
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2013 (English)In: Journal of Molecular Neuroscience, ISSN 0895-8696, E-ISSN 1559-1166, Vol. 51, no 2, p. 615-628Article in journal (Refereed) Published
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.

Keywords
Acetylation, Avian, Chromatin structure, Development, HAT, HDAC, Isoform, Histon, MRG15, MRGX, Neuron, RCAS, Retina, Splicing, Virus vector
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-209850 (URN)10.1007/s12031-013-0034-4 (DOI)000324637200047 ()
Available from: 2013-10-28 Created: 2013-10-28 Last updated: 2017-12-06Bibliographically approved
Boije, H., Shirazi Fard, S., Ring, H. & Hallböök, F. (2013). Forkheadbox N4 (FoxN4) triggers context-dependent differentiation in the developing chick retina and neural tube. Differentiation, 85(1-2), 11-19
Open this publication in new window or tab >>Forkheadbox N4 (FoxN4) triggers context-dependent differentiation in the developing chick retina and neural tube
2013 (English)In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 85, no 1-2, p. 11-19Article in journal (Refereed) Published
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.

Keywords
Chicken, Lim1, Prox1, Retinal development, Retinal progenitor cells, Sox2
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-195033 (URN)10.1016/j.diff.2012.12.002 (DOI)000318393700002 ()
Available from: 2013-02-21 Created: 2013-02-20 Last updated: 2017-12-06Bibliographically approved
Ka, S., Markljung, E., Ring, H., Albert, F. W., Harun-Or-Rashid, M., Wahlberg, P., . . . Hallböök, F. (2013). The expression of carnitine palmitoyl-CoA transferase-1B is influenced by a cis-acting eQTL in two chicken lines selected for high and low body weight. Physiological Genomics, 45(9), 367-376
Open this publication in new window or tab >>The expression of carnitine palmitoyl-CoA transferase-1B is influenced by a cis-acting eQTL in two chicken lines selected for high and low body weight
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2013 (English)In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 45, no 9, p. 367-376Article in journal (Refereed) Published
Abstract [en]

Carnitine palmitoyl-CoA transferase-1B is a mitochondrial enzyme in the fatty acid oxidation pathway. In a previous study, CPT1B was identified as differentially expressed in the hypothalamus of two lines of chickens established by long-term selection for high (HWS) or low (LWS) body weight. Mammals have three paralogs (CPT1a, b and c) while non-mammalian vertebrates only have two (CPT1A, B). CPT1A is expressed in liver and CPT1B in muscle. CPT1c is expressed in hypothalamus, where it regulates feeding and energy expenditure. We identified an intronic length polymorphism, fixed for different alleles in the two populations and mapped the hitherto missing CPT1B locus in the chicken genome assembly, to the distal tip of chromosome 1p. Based on molecular phylogeny and gene synteny we suggest that chicken CPT1B is pro-orthologous of the mammalian CPT1c. Chicken CPT1B was differentially expressed in both muscle and hypothalamus but in opposite directions: higher levels in hypothalamus but lower levels in muscle in the HWS than in the LWS line. Using an advanced inter-cross population of the lines, CPT1B expression was found to be influenced by a cis-acting expression quantitative trait locus in muscle. The increased expression in hypothalamus and reduced expression in muscle is consistent with an increased food intake in the HWS line and at the same time reduced fatty acid oxidation in muscle yielding a net accumulation of energy intake and storage. The altered expression of CPT1B in hypothalamus and peripheral tissue is likely to be a mechanism contributing to the remarkable difference between lines.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-197716 (URN)10.1152/physiolgenomics.00078.2012 (DOI)000318265700003 ()23512741 (PubMedID)
Available from: 2013-04-02 Created: 2013-04-02 Last updated: 2017-12-06Bibliographically approved
Ring, H. (2012). Characterization of Retinal Progenitor Cells: Focus on Proliferation and the GABAA Receptor System. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Characterization of Retinal Progenitor Cells: Focus on Proliferation and the GABAA Receptor System
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

One strategy to repair an injured or degenerated retina is to stimulate the replacement of damaged or dead neurons with cells derived from endogenous stem- or progenitor cells. A successful strategy requires knowledge about how the proliferation and differentiation of the endogenous cells are regulated. In particular, this knowledge will be important in the establishment of protocols that produce sufficient numbers of specific neurons. The main aim of this thesis was to find and characterise factors regulating the proliferation and differentiation of retinal progenitor cells (RPCs) and hence, contribute to the knowledge of how to use progenitor cells for retinal repair.   

The major result in this thesis is that GABA contributes to and maintains RPC proliferation. Inhibition of GABAA receptors decreases the proliferation of non-pigmented ciliary epithelial (NPE) cells and RPCs in the intact retina. We propose that this effect is mediated through changes in the membrane potential and voltage-gated calcium channels, which in turn regulate components of the cell cycle. Furthermore, we show that one of the endogenous RPC sources, the Müller cells, consists of two subpopulations based on Pax2 expression. This is interesting because Pax2 may suppress the neurogenic potential, characterised by de-differentiation and proliferation, in Müller cells. Finally, we show that over-expression of FoxN4 induces differentiation-associated transcription factors in the developing chick retina. However, FoxN4 over-expression did not trigger differentiation of NPE cells. These results indicate that the intrinsic properties of the RPCs are determinant for FoxN4-induced differentiation.

The results presented in this thesis advance our understanding of how specific cells may be generated from different sources of RPCs. Our results show that the different sources are highly diverse in their potential to proliferate and produce neurons. GABA, Pax2 and FoxN4 may be factors to consider when designing strategies for retinal repair. However, the results indicate that the specific responses to these factors are highly associated with the specific properties of the progenitor cells.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. p. 60
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 821
Keywords
Regeneration, Proliferation, Neurotransmitters, Müller cells, Differentiation, Retinal repair, Neurogenesis
National Category
Neurosciences Other Basic Medicine
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-180011 (URN)978-91-554-8489-7 (ISBN)
Public defence
2012-12-13, B41, BMC, Husargatan 3, Uppsala, 10:00 (English)
Opponent
Supervisors
Note

Doctor of Philosophy (Faculty of Medicine)

Available from: 2012-11-22 Created: 2012-08-28 Last updated: 2018-01-12Bibliographically approved
Ring, H., Mendu, S. K., Shirazi-Fard, S., Birnir, B. & Hallböök, F. (2012). GABA maintains the proliferation of progenitors in the developing chick ciliary marginal zone and non-pigmented ciliary epithelium:      . PLoS ONE, 7(5), e36874
Open this publication in new window or tab >>GABA maintains the proliferation of progenitors in the developing chick ciliary marginal zone and non-pigmented ciliary epithelium:      
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, p. e36874-Article in journal (Refereed) Published
Abstract [en]

GABA is more than the main inhibitory neurotransmitter found in the adult CNS. Several studies have shown that GABA regulates the proliferation of progenitor and stem cells. This work examined the effects of the GABA(A) receptor system on the proliferation of retinal progenitors and non-pigmented ciliary epithelial (NPE) cells. qRT-PCR and whole-cell patch-clamp electrophysiology were used to characterize the GABA(A) receptor system. To quantify the effects on proliferation by GABA(A) receptor agonists and antagonists, incorporation of thymidine analogues was used. The results showed that the NPE cells express functional extrasynaptic GABA(A) receptors with tonic properties and that low concentration of GABA is required for a baseline level of proliferation. Antagonists of the GABA(A) receptors decreased the proliferation of dissociated E12 NPE cells. Bicuculline also had effects on progenitor cell proliferation in intact E8 and E12 developing retina. The NPE cells had low levels of the Cl-transporter KCC2 compared to the mature retina, suggesting a depolarising role for the GABA(A) receptors. Treatment with KCl, which is known to depolarise membranes, prevented some of the decreased proliferation caused by inhibition of the GABA(A) receptors. This supported the depolarising role for the GABA(A) receptors. Inhibition of L-type voltage-gated Ca2+ channels (VGCCs) reduced the proliferation in the same way as inhibition of the GABA(A) receptors. Inhibition of the channels increased the expression of the cyclin-dependent kinase inhibitor p27(KIP1), along with the reduced proliferation. These results are consistent with that when the membrane potential indirectly regulates cell proliferation with hyperpolarisation of the membrane potential resulting in decreased cell division. The increased expression of p27(KIP1) after inhibition of either the GABA(A) receptors or the L-type VGCCs suggests a link between the GABA(A) receptors, membrane potential, and intracellular Ca2+ in regulating the cell cycle. 

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-172512 (URN)10.1371/journal.pone.0036874 (DOI)000305336100070 ()
Available from: 2012-04-11 Created: 2012-04-10 Last updated: 2018-01-12Bibliographically approved
Ring, H., Boije, H., Daniel, C., Ohlson, J., Öhman, M. & Hallböök, F. (2010). Increased A-to-I RNA editing of the transcript for GABAA receptor subunit α3 during chick retinal development. Visual Neuroscience, 27(5-6), 149-157
Open this publication in new window or tab >>Increased A-to-I RNA editing of the transcript for GABAA receptor subunit α3 during chick retinal development
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2010 (English)In: Visual Neuroscience, ISSN 0952-5238, E-ISSN 1469-8714, Vol. 27, no 5-6, p. 149-157Article in journal (Refereed) Published
Abstract [en]

Adenosine-to-inosine (A-to-I) RNA editing is a cotranscriptional or posttranscriptional gene regulatory mechanism that increases the diversity of the proteome in the nervous system. Recently, the transcript for GABA type A receptor subunit α3 was found to be subjected to RNA editing. The aim of this study was to determine if editing of the chicken α3 subunit transcript occurs in the retina and if the editing is temporally regulated during development. We also raised the question if editing of the α3 transcript was temporally associated with the suggested developmental shift from excitation to inhibition in the GABA system. The editing frequency was studied by using Sanger and Pyrosequencing, and to monitor the temporal aspects, we studied the messenger RNA expression of the GABAA receptor subunits and chloride pumps, known to be involved in the switch. The results showed that the chick α3 subunit was subjected to RNA editing, and its expression was restricted to cells in the inner nuclear and ganglion cell layer in the retina. The extent of editing increased during development (after embryonic days 8–9) concomitantly with an increase of expression of the chloride pump KCC2. Expression of several GABAA receptor subunits known to mediate synaptic GABA actions was upregulated at this time. We conclude that editing of the chick GABAA subunit α3 transcript in chick retina gives rise to an amino acid change that may be of importance in the switch from excitatory to inhibitory receptors.

Keywords
Chloride ion channel, GABA(A) subunits, GABA receptor, KCC2, mRNA expression, Posttranscriptional modification
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-143655 (URN)10.1017/S0952523810000180 (DOI)000285477900002 ()20843408 (PubMedID)
Available from: 2011-01-24 Created: 2011-01-24 Last updated: 2017-12-11Bibliographically approved
Boije, H., Ring, H., Lopez-Gallardo, M., Prada, C. & Hallböök, F. (2010). Pax2 Is Expressed in a Subpopulation of Muller Cells in the Central Chick Retina. Developmental Dynamics, 239(6), 1858-1866
Open this publication in new window or tab >>Pax2 Is Expressed in a Subpopulation of Muller Cells in the Central Chick Retina
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2010 (English)In: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 239, no 6, p. 1858-1866Article in journal (Refereed) Published
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.

Keywords
avascular, development, EdU, glia, Muller glia, regeneration, Sox2, zebrafish
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-136282 (URN)10.1002/dvdy.22309 (DOI)000278761700027 ()
Available from: 2010-12-11 Created: 2010-12-11 Last updated: 2017-12-11Bibliographically approved
Boije, H., Shirazi Fard, S., Ring, H. & Hallböök, F. Forkhead box N4 (FoxN4) triggers context-dependent differentiation in the developing chick retina and neural tube. Differentiation
Open this publication in new window or tab >>Forkhead box N4 (FoxN4) triggers context-dependent differentiation in the developing chick retina and neural tube
(English)In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436Article in journal (Refereed) Submitted
Keywords
Chicken, retinal development, Lim1, Prox1, retinal progenitor cells, Sox2
National Category
Neurosciences
Research subject
Developmental Neurosciences
Identifiers
urn:nbn:se:uu:diva-180007 (URN)
Available from: 2012-08-28 Created: 2012-08-28 Last updated: 2018-01-12Bibliographically approved
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