Math5 is required for retinal ganglion cell and optic nerve formation

The vertebrate retina contains seven major neuronal and glial cell types in an interconnected network that collects, processes and sends visual signal s through the optic nerve to the brain, Retinal neuron differentiation is t hought to require both intrinsic and extrinsic factors, yet few intrinsic g ene products have been identified that direct this process. Math5 (Atoh7) e ncodes a basic helix-loop-helix (bHLH) transcription factor that is specifi cally expressed by mouse retinal progenitors. Math5 is highly homologous to atonal, which is critically required for R8 neuron formation during Drosop hila eye development. Like R8 cells in the fly eye, retinal ganglion cells (RGCs) are the first neurons in the vertebrate eye. Here we show that Math5 mutant mice are fully viable, yet lack RGCs and optic nerves. Thus, two ev olutionarily diverse eye types require atonal gene family function for the earliest stages of retinal neuron formation. At the same time, the abundanc e of cone photoreceptors is significantly increased in Math5(-/-) retinae, suggesting a binary change in cell fate from RGCs to cones. A small number of nascent RGCs are detected during embryogenesis, but these fail to develo p further, suggesting that committed RGCs may also require Math5 function.