Stimulation of Retinal Regeneration

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Abstract ! Like other areas of the nervous system, the retina is subject to many acquired and inherited neuronal degenerative diseases. Since the retina provides the input for all visual sensory information to the brain, the loss of cells results in visual impairment and potentially complete blindness. Many retinal degenerative diseases affect only a subset of the retinal cells, although, frequently in more advanced disease, loss and reorganization of the entire retina can occur. In mammals, there is very limited regeneration of the degenerated cells; however, in fish, new neurons of all types regenerate from Müller glia (MG) following retinal damage and they are functionally integrated into the existing circuitry. Although mammals, including people, lack this ability, MG, the cellular source for regeneration, are present in all vertebrate retinas. We hypothesize that regeneration from mammalian MG is limited because they fail to express the proneural program of gene expression after injury. We have found that viral over-expression of a proneural transcription factor can partly reprogram mammalian MG to a neurogenic state in vitro. For in vivo confirmation, we generated a transgenic mouse to express Ascl1 in MG. When we induce Ascl1 expression in adult MG, the combination of Ascl1 and histone deacetylase (HDAC) inhibition can stimulate new neuron production from MG in adult mice after NMDA induced damage. The MG-derived neurons primarily resemble bipolar or amacrine cells, and form connections with the existing retinal circuitry. These results show for the first time that functional neurons can be regenerated in an adult mammalian retina and properly integrate within the existing host circuit, but raise a key question: Why do the MG only produce bipolar cells and amacrine cells? In this proposal we outline studies to better understand, and potentially overcome, the barriers to regeneration in mammalian retina. !