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L. Prasov, T. Glaser; Math5 Confers Multipotency to Fate-Restricted Post-Mitotic Retinal Precursors. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1310.
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The Math5 (Atoh7) basic helix-loop-helix transcription factor is transiently expressed during early retinal histogenesis in a subset of newly post-mitotic precursors. These form 5% of the adult retina, including the first-born cell type, the retinal ganglion cells (RGCs). Math5 is necessary, but not sufficient, for RGC development. In lineage tracing experiments, Math5+ cells develop into all 7 major retinal cell types, and only 10% become RGCs. Here, we investigate the role of Math5 as an RGC competence factor by expressing it in a wide population of fate-restricted post-mitotic retinal precursors.
We generated Crx>Math5-ires-Cre mice using the 2.4 kb Crx promoter to express Math5 and Cre recombinase from a single bicistronic transcript. Previous Crx>Cre and Crx>lacZ studies show that Crx is normally expressed by photoreceptors and bipolar cells, beginning shortly after terminal mitosis. We examined the properties and fates of Crx>Math5+ cells at several time points during development, using the ROSA26-flox-GFP reporter.
In 4 independent Crx>Math5-ires-Cre transgenic lines, we observed lineage-labeled cells among all retinal cell types, including RGCs. In these mice, Cre and endogenous Crx are co-expressed in post-mitotic cells throughout development. Despite this large-scale reassignment of fates, involving 90% of the neural retina, RGCs are produced in normal abundance and have birthdates before P1. Adult photoreceptor and bipolar cells continue to express Math5, but the retinal histology appears normal.
Math5 can restore multipotency to fate-restricted post-mitotic retinal precursors. These cells exhibit greater plasticity than previously thought. Our results highlight the robust homeostatic mechanisms that ensure the proper ratio of cell types during retinal development.
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