The retina is one of the most accessible parts of the central nervous system and has served as a wonderful model for addressing how cell fate is determined. We are using both Xenopus laevis and mouse to define at a molecular level the essential steps in the life of a progenitor cell as it progresses towards a specific retinal neuron fate.An important theme of our work is to understand the interplay between transcription factors that regulate neural differentiation in the retina and extrinsic signaling pathways that modulate their expression or function, resulting in changes in gene expression and thus in cell fate. For example, we have been investigating the mechanisms by which proneural transcription factors promote retinal neuron differentiation, and how they contribute to the ordered sequence of retinal histogenesis. We find that both the expression and activity of these factors are controlled multiple signaling pathways. For example, we recently showed that Wnt signaling through the Fz5 receptor regulates the expression of Sox2, which is required for neural competence and the expression of proneural factors in the developing eye. Ultimately, the goal is to reveal general principles governing the development of neural stem cells and progenitors, which may inform efforts to harness these cells for the treatment of disease and injury of the nervous system. In that vein, we are investigating the mechanisms underlying a devastating degenerative disease of the retina, namely glaucoma, which is characterized by progressive loss of retinal ganglion cells (RGCs) leading to blindness. We are focusing our efforts on understanding the changes that take place at early stages of disease using an inbred mouse strain that develops glaucoma-like pathology (DBA/2J). We find that glaucoma shares many of the hallmark features of other neurodegenerative diseases, including significant involvement of microglia. We have also found early down-regulation of key regulatory genes within RGCs themselves, and are determining how their loss contributes to changes in the viability of RGCs. Because of these common features, glaucoma may offer a tractable system for understanding how neural tissue responds to stress or injury and degenerates over time.