The basic helix-loop-helix gene hesr2 promotes gliogenesis in mouse retina

Members of a subclass of hairy/Enhancer of split [E(spl)] homologs, called hesr genes, are structurally related to another subclass of hairy/E(spl) ho mologs, Hes genes, which play an important role in neural development. To c haracterize the roles of hesr genes in neural development, we used the reti na as a model system. In situ hybridization analysis indicated that all hes r genes are expressed in the developing retina, but only hesr2 expression i s associated spatially with gliogenesis. Each member was then misexpressed with retrovirus in the retinal explant cultures prepared from mouse embryos or neonates, which well mimic in vivo retinal development. Interestingly, hesr2 but not hesr1 or hesr3 promoted gliogenesis while inhibiting rod gene sis without affecting cell proliferation or death, suggesting that the cell s that normally differentiate into rods adopted the glial fate by misexpres sion of hesr2. The gliogenic activity of hesr2 was more profound when it wa s misexpressed postnatally than prenatally. In addition, double mutation of the neuronal determination genes Mash1 and Math3, which increases Muller g lia at the expense of bipolar cells, upregulated hesr2 expression. These re sults indicate that, among structurally related hesr genes, only hesr2 prom otes glial versus neuronal cell fate specification in the retina and that a ntagonistic regulation between hesr2 and Mash1-Math3 may determine the rati os of neurons and glia.