Math5 defines the ganglion cell competence state in a subpopulation of retinal progenitor cells exiting the cell cycle

The basic helix-loop-helix (bHLH) transcription factor . Math5 (. Atoh7) is transiently expressed during early retinal histogenesis and is necessary for retinal ganglion cell (RGC) development. Using nucleoside pulse-chase experiments and clonal analysis, we determined that progenitor cells activate . Math5 during or after the terminal division, with progressively later onset as histogenesis proceeds. We have traced the lineage of . Math5+ cells using mouse BAC transgenes that express Cre recombinase under strict regulatory control. Quantitative analysis showed that . Math5+ progenitors express equivalent levels of . Math5 and contribute to every major cell type in the adult retina, but are heavily skewed toward early fates. The Math5. >. Cre transgene labels 3% of cells in adult retina, including 55% of RGCs. Only 11% of . Math5+ progenitors develop into RGCs; the majority become photoreceptors. The fate bias of the . Math5 cohort, inferred from the ratio of cone and rod births, changes over time, in parallel with the remaining neurogenic population. Comparable results were obtained using . Math5 mutant mice, except that ganglion cells were essentially absent, and late fates were overrepresented within the lineage. We identified . Math5-independent RGC precursors in the earliest born (embryonic day 11) retinal cohort, but these precursors require . Math5-expressing cells for differentiation. . Math5 thus acts permissively to establish RGC competence within a subset of progenitors, but is not sufficient for fate specification. It does not autonomously promote or suppress the determination of non-RGC fates. These data are consistent with progressive and temporal restriction models for retinal neurogenesis, in which environmental factors influence the final histotypic choice.