RESUMO
Retinal stem cells [with the potential to produce either neural retinal progenitors or retinal pigment epithelial (RPE) progenitors] exist in the mammalian eye throughout life, and indeed the greatest absolute increase in the stem population occurs postnatally. The stem cells proliferate embryonically and thus may help to build the retina initially, but in postnatal mammals they clearly do not proliferate to regenerate the retina in response to injury. Using Chx10(orJ/orJ) and Mitf(mi/mi) mice, with small eye phenotypes due to the reduction of the neural retinal progenitor population and the retinal pigmented epithelial progenitor population, respectively, we now report that the retinal stem cell population, when assayed from the ciliary margin, increases 3-8-fold in both mutants. These findings suggest that the mammalian retinal stem cell population may be capable of responding to genetically induced signals from the progenitor populations.
Assuntos
Olho , Epitélio Pigmentado Ocular/fisiologia , Retina/citologia , Células-Tronco/fisiologia , Animais , Animais Recém-Nascidos , Contagem de Células/métodos , Diferenciação Celular/genética , Embrião de Mamíferos , Olho/citologia , Olho/embriologia , Olho/crescimento & desenvolvimento , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Camundongos , Camundongos Mutantes , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição Associado à Microftalmia/metabolismo , Modelos Biológicos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
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.
