| Mammalian retina is a highly organized layered structure consisting of multiple discrete neuronal cell types. The mechanisms underlying the sequential specifications of the cell fate of distinct retinal cells are not completely understood. However, it has been suggested that the intrinsic properties of uncommitted retinal progenitors undergo a series of alterations so that they are competent for the generation of one or a few distinct retinal cell types at a given developmental stage. The determination of individual competent states is achieved by the expression of unique sets of transcription factors.; bHLH transcription factors are extensively involved in the differentiation of a variety of tissues and cellular lineages. Math5, the mouse homolog of Drosophila Atonal, is required for RGC generation. Deletion of math5 in mice results in the failure of RGC formation, and a concomitant increase in amacrine cells and cone photoreceptors. However, it remains unclear how Math5 regulates retinal cell fate specification.; In study one, we conducted a detailed investigation of how math5 may control retinal neurogenesis. We confirmed that most RGCs were missing in math5-null retina. In addition, the formation of cone photoreceptor cells is promoted in the absence of math5. Moreover, we demonstrated that a portion of OFF-centered cone bipolar cells were selectively ablated in math5 knockout mice.; In study two, we employed the Cre-loxP system to explore the lineage-specific involvement of math5 in retinal neurogenesis. By genetically tracing the cell fates of math5-expressing retinal precursor cells, we demonstrated that Math5-positive precursors can generate multiple discrete lineages including RGC, amacrine, horizontal, and photoreceptor cells, but not bipolar cells and Muller glia. Together with evidence of a requirement of math5 for RGC formation, we conclude that the Math5 is a prerequisite but not a lineage-specifying factor for RGC formation, and postmitotic retinal precursor cells acquire the competent state for the generation of RGC by the transient activation of math5 expression. In addition, we provided evidence supporting that the function of the Drosophila ato/senseless pathway in specifying R8 photoreceptor was partially conserved as the math5/brn-3b/gfi1 cascade in mouse RGC development. |
