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

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.