nacre encodes a zebrafish microphthalmia-related protein that regulates neural-crest-derived pigment cell fate

Development ◽  
1999 ◽  
Vol 126 (17) ◽  
pp. 3757-3767 ◽  
Author(s):  
J.A. Lister ◽  
C.P. Robertson ◽  
T. Lepage ◽  
S.L. Johnson ◽  
D.W. Raible
Keyword(s):  
Transcription Factor ◽  
Retinal Pigment Epithelium ◽  
Neural Crest ◽  
Cell Fate ◽  
Pigment Cell ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Pigment Cells ◽  
Evolutionary Divergence ◽  
Wild Type

We report the isolation and identification of a new mutation affecting pigment cell fate in the zebrafish neural crest. Homozygous nacre (nac(w2)) mutants lack melanophores throughout development but have increased numbers of iridophores. The non-crest-derived retinal pigment epithelium is normal, suggesting that the mutation does not affect pigment synthesis per se. Expression of early melanoblast markers is absent in nacre mutants and transplant experiments suggested a cell-autonomous function in melanophores. We show that nac(w2) is a mutation in a zebrafish gene encoding a basic helix-loop-helix/leucine zipper transcription factor related to microphthalmia (Mitf), a gene known to be required for development of eye and crest pigment cells in the mouse. Transient expression of the wild-type nacre gene restored melanophore development in nacre(−/−) embryos. Furthermore, misexpression of nacre induced the formation of ectopic melanized cells and caused defects in eye development in wild-type and mutant embryos. These results demonstrate that melanophore development in fish and mammals shares a dependence on the nacre/Mitf transcription factor, but that proper development of the retinal pigment epithelium in the fish is not nacre-dependent, suggesting an evolutionary divergence in the function of this gene.

scholarly journals Epigenetic dynamics shaping melanophore and iridophore cell fate in zebrafish

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Hyo Sik Jang ◽  
Yujie Chen ◽  
Jiaxin Ge ◽  
Alicia N. Wilkening ◽  
Yiran Hou ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
Neural Crest ◽  
Cell Fate ◽  
Pigment Cell ◽  
Chromatin Accessibility ◽  
Pigment Cells ◽  
Epigenetic Landscape ◽  
Cell Fate Decisions ◽  
Neural Crest Differentiation

Abstract Background Zebrafish pigment cell differentiation provides an attractive model for studying cell fate progression as a neural crest progenitor engenders diverse cell types, including two morphologically distinct pigment cells: black melanophores and reflective iridophores. Nontrivial classical genetic and transcriptomic approaches have revealed essential molecular mechanisms and gene regulatory circuits that drive neural crest-derived cell fate decisions. However, how the epigenetic landscape contributes to pigment cell differentiation, especially in the context of iridophore cell fate, is poorly understood. Results We chart the global changes in the epigenetic landscape, including DNA methylation and chromatin accessibility, during neural crest differentiation into melanophores and iridophores to identify epigenetic determinants shaping cell type-specific gene expression. Motif enrichment in the epigenetically dynamic regions reveals putative transcription factors that might be responsible for driving pigment cell identity. Through this effort, in the relatively uncharacterized iridophores, we validate alx4a as a necessary and sufficient transcription factor for iridophore differentiation and present evidence on alx4a’s potential regulatory role in guanine synthesis pathway. Conclusions Pigment cell fate is marked by substantial DNA demethylation events coupled with dynamic chromatin accessibility to potentiate gene regulation through cis-regulatory control. Here, we provide a multi-omic resource for neural crest differentiation into melanophores and iridophores. This work led to the discovery and validation of iridophore-specific alx4a transcription factor.

scholarly journals CRISPR knockouts of pmela and pmelb engineered a golden tilapia by regulating relative pigment cell abundance

2021 ◽  
Author(s):  
Chenxu Wang ◽  
Jia Xu ◽  
Thomas D. Kocher ◽  
Minghui Li ◽  
Deshou Wang
Keyword(s):  
Pigment Cell ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Homozygous Mutation ◽  
Body Color ◽  
Wild Type ◽  
Double Mutation ◽  
Vertical Bars ◽  
White Plumage ◽  
New Strategies

Premelanosome protein (pmel) is a key gene for melanogenesis in vertebrates. Mutations in this gene are responsible for white plumage in chicken, but its role in pigmentation of fish remains to be demonstrated. In this study we found that most fishes have two pmel genes arising from the teleost-specific whole genome duplication. Both pmela and pmelb were expressed at high levels in the eyes and skin of Nile tilapia. We mutated both genes in tilapia using CRISPR/Cas9 gene editing. Homozygous mutation of pmela resulted in yellowish body color with weak vertical bars and a hypo-pigmented retinal pigment epithelium (RPE) due to significantly reduced number and size of melanophores. In contrast, we observed an increased number and size of xanthophores in mutants compared to wild-type fish. Homozygous mutation of pmelb resulted in a similar, but milder phenotype than pmela -/- mutants, without effects on RPE pigmentation. Double mutation of pmela and pmelb resulted in loss of additional melanophores compared to the pmela -/- mutants, and also an increase in the number and size of xanthophores, producing a strong golden body color without bars in the trunk. The RPE pigmentation of pmela -/ - ;pmelb -/- was similar to pmela -/- mutants, with much less pigmentation than pmelb -/- mutants and wild-type fish. Taken together, our results indicate that, while both pmel genes are important for the formation of body color in tilapia, pmela plays a more important role than pmelb. To our knowledge, this is the first report on mutation of pmelb or both pmela;pmelb in fish. Studies on these mutants suggest new strategies for breeding golden tilapia, and also provide a new model for studies of pmel function in vertebrates.

scholarly journals Regulation of Prenatal Human Retinal Neurosphere Growth and Cell Fate Potential by Retinal Pigment Epithelium and Mash1

Stem Cells ◽  
2008 ◽  
Vol 26 (12) ◽  
pp. 3182-3193 ◽  
Author(s):  
David M. Gamm ◽  
Lynda S. Wright ◽  
Elizabeth E. Capowski ◽  
Rebecca L. Shearer ◽  
Jason S. Meyer ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Cell Fate ◽  
Pigment Epithelium ◽  
Retinal Pigment

scholarly journals Expression of ABCA4 in the retinal pigment epithelium and its implications for Stargardt macular degeneration

2018 ◽  
Vol 115 (47) ◽  
pp. E11120-E11127 ◽  
Author(s):  
Tamara L. Lenis ◽  
Jane Hu ◽  
Sze Yin Ng ◽  
Zhichun Jiang ◽  
Shanta Sarfare ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Wild Type Mouse ◽  
Mouse Retina ◽  
Sequencing Analysis ◽  
Wild Type ◽  
Rpe Cells ◽  
Photoreceptor Outer Segments ◽  
Quantitative Immunoblotting

Recessive Stargardt disease (STGD1) is an inherited blinding disorder caused by mutations in the Abca4 gene. ABCA4 is a flippase in photoreceptor outer segments (OS) that translocates retinaldehyde conjugated to phosphatidylethanolamine across OS disc membranes. Loss of ABCA4 in Abca4−/− mice and STGD1 patients causes buildup of lipofuscin in the retinal pigment epithelium (RPE) and degeneration of photoreceptors, leading to blindness. No effective treatment currently exists for STGD1. Here we show by several approaches that ABCA4 is additionally expressed in RPE cells. (i) By in situ hybridization analysis and by RNA-sequencing analysis, we show the Abca4 mRNA is expressed in human and mouse RPE cells. (ii) By quantitative immunoblotting, we show that the level of ABCA4 protein in homogenates of wild-type mouse RPE is about 1% of the level in neural retina homogenates. (iii) ABCA4 immunofluorescence is present in RPE cells of wild-type and Mertk−/− but not Abca4−/− mouse retina sections, where it colocalizes with endolysosomal proteins. To elucidate the role of ABCA4 in RPE cells, we generated a line of genetically modified mice that express ABCA4 in RPE cells but not in photoreceptors. Mice from this line on the Abca4−/− background showed partial rescue of photoreceptor degeneration and decreased lipofuscin accumulation compared with nontransgenic Abca4−/− mice. We propose that ABCA4 functions to recycle retinaldehyde released during proteolysis of rhodopsin in RPE endolysosomes following daily phagocytosis of distal photoreceptor OS. ABCA4 deficiency in the RPE may play a role in the pathogenesis of STGD1.

Identification of a Novel Isoform of Microphthalmia-Associated Transcription Factor That Is Enriched in Retinal Pigment Epithelium

1998 ◽  
Vol 247 (3) ◽  
pp. 710-715 ◽  
Author(s):  
Shintaro Amae ◽  
Nobuo Fuse ◽  
Ken-ichi Yasumoto ◽  
Shigeru Sato ◽  
Ichiro Yajima ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Retinal Pigment Epithelium ◽  
Pigment Epithelium ◽  
Retinal Pigment

scholarly journals Absence of iron-regulatory protein Hfe results in hyperproliferation of retinal pigment epithelium: role of cystine/glutamate exchanger

2009 ◽  
Vol 424 (2) ◽  
pp. 243-252 ◽  
Author(s):  
Jaya P. Gnana-Prakasam ◽  
Muthusamy Thangaraju ◽  
Kebin Liu ◽  
Yonju Ha ◽  
Pamela M. Martin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Retinal Pigment Epithelium ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Critical Role ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Mrna Levels ◽  
Wild Type ◽  
Rpe Cells

Haemochromatosis is an iron-overload disorder with age-dependent oxidative stress and dysfunction in a variety of tissues. Mutations in HFE (histocompatability leucocyte antigen class I-like protein involved in iron homoeostasis) are responsible for most cases of haemochromatosis. We demonstrated recently that HFE is expressed exclusively in the basal membrane of RPE (retinal pigment epithelium). In the present study, we used Hfe−/− mice to examine ferritin levels (an indirect readout for iron levels) and morphological changes in retina. We found increased ferritin accumulation in retina in 18-month-old, but not in 2-month-old, mice with considerable morphological damage compared with age-matched controls. The retinal phenotype included hypertrophy and hyperplasia of RPE. RPE cells isolated from Hfe−/− mice exhibited a hyperproliferative phenotype. We also compared the gene expression profile between wild-type and Hfe−/− RPE cells by microarray analysis. These studies showed that many cell cycle-related genes were differentially regulated in Hfe−/− RPE cells. One of the genes up-regulated in Hfe−/− RPE cells was Slc7a11 (where Slc is solute carrier) which codes for the ‘transporter proper’ xCT in the heterodimeric cystine/glutamate exchanger (xCT/4F2hc). This transporter plays a critical role in cellular glutathione status and cell-cycle progression. We confirmed the microarrray data by monitoring xCT mRNA levels by RT (reverse transcription)–PCR and also by measuring transport function. We also found increased levels of glutathione and the transcription factor/cell-cycle promoter AP1 (activator protein 1) in Hfe−/− RPE cells. Wild-type mouse RPE cells and human RPE cell lines, when loaded with iron by exposure to ferric ammonium citrate, showed increased expression and activity of xCT, reproducing the biochemical phenotype observed with Hfe−/− RPE cells.

The T-Box Transcription Factor TBX2 Regulates Cell Proliferation in the Retinal Pigment Epithelium

2017 ◽  
Vol 42 (11) ◽  
pp. 1537-1544 ◽  
Author(s):  
Jing Wang ◽  
Yin Liu ◽  
Zhongyuan Su ◽  
Li Pan ◽  
Fan Lu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcription Factor ◽  
Retinal Pigment Epithelium ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
T Box
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