Transdifferentiation of the ventral retinal pigmented epithelium to neuralretina in the Growth arrest specific gene 1 mutant

During eye development, retinal pigmented epithelium (RPE) and neural retin a (NR) arise from a common origin, the optic vesicle. One of the early dist inctions of RPE from NR is the reduced mitotic activity of the RPE. Growth arrest specific gene 1 (Gas1) has been documented to inhibit cell cycle pro gression in vitro (G. Del Sal et al., 1992, Cell 70, 595-607). We show here that the expression pattern of Gas1 in the eye supports its negative role in RPE proliferation. To test this hypothesis, we generated a mouse carryin g a targeted mutation in the Gas1 locus. Gas1 mutant mice have microphthalm ia. Histological examination revealed that the remnant mutant eyes are ingr essed from the surface with minimal RPE and lens, and disorganized eyelid, cornea, and NR. Analysis of the Gas1 mutant indicates that there is overpro liferation of the outer layer of optic cup (E10.5) immediately after the in itial specification of the RPE. This defect is specific to the ventral regi on of the RPE. Using molecular markers for RPE (Mi and Tyrp2) and NR (Math5 ), we demonstrate that there is a gradual loss of AV and Tyrp2 expression a nd an appearance of Math5 expression in the mutant ventral RPE region, indi cating that this domain becomes respecified to NR. This "ectopic" NR develo ps as a mirror image of the normal NR and is entirely of ventral identity. Our data not only support Gas1's function in regulating cell proliferation, but also uncover an unexpected regional-specific cell fate change associat ed with dysregulated growth. Furthermore, we provide evidence that the dors al and ventral RPEs are maintained by distinct genetic components. (C) 2001 Academic Press.