Regeneration of retinal neurons from Müller glia in adult mice

Abstract

There are many diseases that result in the death of specific neuron populations in the retina, resulting in blindness. Currently, few options exist for the treatment of blinding diseases, and the options that are available can be invasive and only have modest efficacy. Various non-mammalian organisms have the natural ability to regenerate their retinal neurons following injury. The proneural transcription factor, Ascl1, has been shown to be necessary and sufficient to initiate the regenerative process in these species, specifically in the retinal Müller glia. After Ascl1 induction, the Müller glia proliferate, migrate, and differentiate into all subtypes of retinal neurons and even integrate into the retinal circuitry, fully restoring function to the animal. I have identified a method for stimulating the regeneration of specific neuron subtypes in mammals by overexpressing Ascl1 in the Müller glia of adult mice. These Müller glial-derived neurons resemble nascent retinal neurons at the morphological, protein, RNA, and epigenetic levels. Additionally, the newly generated neurons integrate into the existing retinal circuitry and response to light stimuli similar to nascent neurons. In this dissertation, I will discuss how we achieved retinal regeneration in adult mice and studies that were performed to further improve and characterize the Müller glia-derived neurons.