Chx10 repression of Mitf is required for the maintenance of mammalian neuroretinal identity.
During vertebrate eye development, the cells of the optic vesicle (OV) become either neuroretinal progenitors expressing the transcription factor Chx10, or retinal pigment epithelium (RPE) progenitors expressing the transcription factor Mitf. Chx10 mutations lead to microphthalmia and impaired neuroretinal proliferation. Mitf mutants have a dorsal RPE-to-neuroretinal phenotypic transformation, indicating that Mitf is a determinant of RPE identity. We report here that Mitf is expressed ectopically in the Chx10(or-J/or-J) neuroretina (NR), demonstrating that Chx10 normally represses the neuroretinal expression of Mitf. The ectopic expression of Mitf in the Chx10(or-J/or-J) NR deflects it towards an RPE-like identity; this phenotype results not from a failure of neuroretinal specification, but from a partial loss of neuroretinal maintenance. Using Chx10 and Mitf transgenic and mutant mice, we have identified an antagonistic interaction between Chx10 and Mitf in regulating retinal cell identity. FGF (fibroblast growth factor) exposure in a developing OV has also been shown to repress Mitf expression. We demonstrate that the repression of Mitf by FGF is Chx10 dependent, indicating that FGF, Chx10 and Mitf are components of a pathway that determines and maintains the identity of the NR.
Horsford
D Jonathan
DJ
Program in Developmental Biology, The Research Institute, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Nguyen
Minh-Thanh T
MT
Sellar
Grant C
GC
Kothary
Rashmi
R
Arnheiter
Heinz
H
McInnes
Roderick R
RR
D000818:Animals; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005123:Eye / Q000196:embryology; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000502:physiology*; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051739:Microphthalmia-Associated Transcription Factor; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology*; D019076:Transgenes
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D014157:Transcription Factors; C088975:Vsx2 protein, mouse