Abstract
During vertebrate eye development, the transcription factor MITF acts to promote the development of the retinal pigment epithelium (RPE). In embryos with Mitf mutations, the future RPE hyperproliferates and is respecified as retinal tissue but only in a small portion of the dorsal RPE. Using a series of genetic crosses, we show that this spatial restriction of RPE respecification is brought about by persistent expression of the anti-retinogenic ventral homeodomain gene Vax2 in the dorso-proximal and both Vax1 and Vax2 in the ventral RPE. We further show that dorso-proximal RPE respecification in Vax2/Mitf double mutants and dorso-proximal and ventral RPE respecification in Vax1/2/Mitf triple mutants result from increased FGF/MAP kinase signaling. In none of the mutants, however, does the distal RPE show signs of hyperproliferation or respecification, likely due to local JAGGED1/NOTCH signaling. Expression studies and optic vesicle culture experiments also suggest a role for NOTCH signaling within the mutant dorsal RPE domains, where ectopic JAGGED1 expression may partially counteract the effects of FGF/ERK1/2 signaling on RPE respecification. The results indicate the presence of complex interplays between distinct transcription factors and signaling molecules during eye development and show how RPE phenotypes associated with mutations in one gene are modulated by expression changes in other genes.
Highlights
An ideal model to study domain specification during vertebrate central nervous system development is provided by the development of the eye
This retinal pigment epithelium (RPE) portion expressed the retinal marker VSX2 (Figure 1L, arrow) and eventually developed as a laminated second retina as previously described [8,19]. In such mutants, VAX1 was more prominent in the ventral RPE at E10.5 (Figure 1Q) where it stayed on at E12.5, and VAX2 was more prominent in the dorso-proximal RPE at E10.5 (Figure 1W) and in both the dorso-proximal and all of the ventral RPE at E12.5
It is well established that mutations of mouse Mitf and its orthologs in other species lead to abnormalities in the RPE that include loss of pigmentation, hyperproliferation, and eventual differentiation of a small dorsal subdomain as a second retina instead of RPE [4,23,25,41,42]
Summary
An ideal model to study domain specification during vertebrate central nervous system development is provided by the development of the eye. Loss-of-function mutations in Mitf result in loss of pigmentation of the entire RPE combined with hyperproliferation and respecification of a small subdomain of the dorsal RPE as neuroretina [7,8]. This suggests either that only the dorsal domain of the mutant RPE is exposed to retinogenic inducers that are strong enough to promote retinal development in the absence of Mitf, or that the remainder of the Mitf mutant RPE is subject to compensatory mechanisms that prevent full RPE-toretina transitions
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