Gbx2 regulates the development of an atypical amacrine cell.

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PROJECT SUMMARY There are more than 100 distinct neuronal subtypes within the mammalian retina. Recent studies have made significant progress in our understanding of how specific neuron subtypes develop, wire into functional circuits, and contribute to disease. However, genetic tools to label and manipulate single populations of neurons only exist for a small proportion of retinal neurons. Using a genetic approach, I have identified a single population of retinal neurons based on their selective expression of the transcription factor Gbx2. These cells are amacrine cells (ACs) and have several interesting properties. Gbx2+ ACs do not express the inhibitory neurotransmitters, GABA or Glycine. Rather, Gbx2+ ACs exhibit gap junction coupled connections to bipolar cells, suggesting that the primary synaptic output for these ACs may be through electrical synapses. I will analyze the development of Gbx2+ ACs to investigate the role of Gbx2 in their cellular identity, morphology, and connectivity. In Aim 1, using a Gbx2 conditional knockout mouse, I will determine how Gbx2 regulates the morphology and electrical coupling of Gbx2+ ACs. I will also identify the specific connexins that mediate electrical synapse formation in Gbx2+ ACs. In Aim 2, I will perform RNAseq analyses in control and Gbx2 conditional knockout ACs to reveal their molecular profile and identify the specific effectors of Gbx2. I will also test the hypothesis that Gbx2 functions as a terminal fate selector to by regulating the expression of genes that endow Gbx2+ ACs with their unique characteristics. My preliminary data indicate that this occurs in part through the regulation of Robo receptors, which guide the proper stratification of Gbx2+ AC dendrites within the retina. This study will provided a comprehensive analysis of the morphological and molecular properties of a previously unidentified amacrine cell, and will elucidate how Gbx2 regulates the development and function of these neurons. The results of this study will lead to the generation of genetic tools and targets that will be useful for future investigations of retina development in health and disease.