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Maintenance and Survival in a Non-Image-Forming Subset of Retinal Ganglion Cells

Creative Commons 'BY' version 4.0 license

The retina detects the visual scene and coverts the information into separate channels of information. These channels then connect to diverse areas in the brain that initiate appropriate visually responsive behaviors. Retinal ganglion cells (RGCs) are the output neurons of the retina and come in ~30 different types, each with distinct receptive eld properties generated by circuits within the retina. Each RGC type processes a distinct feature of the visual scene making up a unique channel of visual information and tranferring it to the appropriate area of the brain. Intriguingly, all the RGC types arise from one common RGC progenitor cell. One of the questions in vision neuroscience is how does this diversity arise during development? Further, once the different RGC types have been speci ed, how do they maintain their identity? Answers to these questions will shed light on the mechanisms that set up the parallel channels of visual information and how visual circuitry is established.

Studies on the gene regulatory network that specifies RGCs have so far yielded several transcription factors that are involved. However, many other transcription factors could be involved in specifying, and then maintaining, the diversity of RGC types. A transcription factor called Tbr2 has been demontrated to be required for specifying a subset of RGCs. In my thesis work I have tested the hypothesis that

Tbr2 is also required for maintaining the identity of that RGC subset. Through loss of function and ectopic expression experiments in adult mice I demonstrate that Tbr2 has an epistatic relationship to melanopsin and is required to maintain the melanopsin- expression aspect of RGCs.

Another aspect of RGC identity is the response to axonal damage. Some RGC types are able to withstand axonal injury and resist death, while other types activate pro-apoptotic pathways within a very short time of the injury and die. The mechanisms responsible for this variation in response to injury is an important factor in understanding the pathogenesis of glaucoma, which is a disease that affects the retinal ganglion cells. There is evidence that the OFF RGCs are more susceptible to apoptosis following optic nerve injury, but still more work needs to be done in classifying RGC types and their response after damage. Melanopsin- expressing RGCs have also been found to survive better than other types following optic nerve injury. Considering that the transcription factor Tbr2 is expressed in all melanopsin RGCs, and that Tbr2 is required for RGC survival during development, I tested the hypothesis that Tbr2-expressing class of RGCs survive better following optic nerve injury as compared to other RGC types. My results show that Tbr2-expressing RGCs do survive better than other RGC types, however not due to Tbr2 expression. This implies the neuroprotective aspect of Tbr2- expressing RGCs is regulated by other factors, and future RNA-seq experiments will help reveal the genes involved.

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