Journal
DEVELOPMENT
Volume 135, Issue 6, Pages 1169-1178Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.014142
Keywords
retina; Retinal pigment epithelium; Mitf red-eyed white; Mitf black-eyed white; Chx10-ocular retardation; internal start codons
Categories
Funding
- Intramural NIH HHS [Z01 NS002790-19] Funding Source: Medline
- Telethon [TCP99018] Funding Source: Medline
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During vertebrate eye development, the transcription factor MITF plays central roles in neuroepithelial domain specification and differentiation of the retinal pigment epithelium. MITF is not a single protein but represents a family of isoforms generated from a common gene by alternative promoter/exon use. To address the question of the role and regulation of these isoforms, we first determined their expression patterns in developing mouse eyes and analyzed the role of some of them in genetic models. We found that two isoforms, A- and J-Mitf, are present throughout development in both retina and pigment epithelium, whereas H-Mitf is detected preferentially and D-Mitf exclusively in the pigment epithelium. We further found that a genomic deletion encompassing the promoter/exon regions of H-, D- and B-Mitf leads to novel mRNA isoforms and proteins translated from internal start sites. These novel proteins lack the normal, isoform-specific N-terminal sequences and are unable to support the development of the pigment epithelium, but are capable of inducing pigmentation in the ciliary margin and the iris. Moreover, in mutants of the retinal Mitf regulator Chx10 (Vsx2), reduced cell proliferation and abnormal pigmentation of the retina are associated with a preferential upregulation of H- and D-Mitf. This retinal phenotype is corrected when H- and D- Mitf are missing in double Mitf/Chx10 mutants. The results suggest that Mitf regulation in the developing eye is isoform-selective, both temporally and spatially, and that some isoforms, including H- and D-Mitf, are more crucial than others in effecting normal retina and pigment epithelium development.
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