The overall goal of this ongoing research program is to understand the molecular basis of cell-cell interactions that regulate retinal neurogenesis during development and regeneration. The zebrafish (Danio rerio) provides a powerful genetic model in which to define the causal relationships between retinal stem cells and the in vivo microenvironment that support neuronal regeneration and restoration of functional neural circuits in the retina of an adult organism. The concept that retinal neurons and MOiler glia derive from a common progenitor in the developing retina is widely accepted, and it is known that late stage retinal progenitors can generate both rod photoreceptors and MOiler glia. More surprising is the recent discovery that differentiated MOiler glia continue to function as neuronal progenitors, producing rod photoreceptors in the uninjured, adult teleost retina. In response to loss of retinal neurons, MOiler glia in the teleost retina dedifferentiate, reenter the cell cycle and generate multipotent retinal progenitors that generate neurons to repair the damage. A latent and abortive neurogenic capacity of MOiler glia in adult mammalian retinas has been demonstrated, however, almost nothing is known about the molecular regulation that switches MOiler glia from a state of reactive gliosis to neurogenesis. The proposed studies take advantage of zebrafish genetics to discover the cellular and molecular mechanisms that promote the endogenous neurogenic potential of MOiler glia.
The specific aims of the proposed research are to evaluate whether candidate regulatory signaling pathways (Wntlp-catenin, Fgf and Notch) acting upstream of the proneural transcription factor ascl1a are required to activate a neurogenic program in MOiler glia, and to evaluate the hypothesis that epithelial characteristics related to apical-basal polarity regulate the neurogenic response of MOiler glia.
The knowledge gained from these studies will assist the development of therapeutic strategies for regenerative medicine with the goal of activating a neurogenic program in retinal M?ller glia to replace neurons lost in damaged or diseased human retinas.
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