Populations of neurons vary in their demographics: They differ in their absolute numbers, in their intercellular spacing and the patterning this produces, in their degree of dendritic overlap and its regulation, and in their synaptic connectivity and the convergence ratios associated with their afferent neurons. The present research program has been addressing the causal relationships associated with such neuronal population dynamics, using the retina as a model system and working with a panel of twenty-six genetically distinct recombinant inbred (RI) mouse strains. Neuron number has been shown to vary considerably across these strains of mice, for twelve different classes of retinal neuron, and this variation maps to discrete genomic loci (quantitative trait loci, or QTL) for each cell type, showing minimal evidence for genomic co-regulation. The genetic sources of this variation in neuron number will be defined, for each cell type, and the developmental roles of these genes modulating cell number will be identified. Independent of neuron number, neurons vary in other histotypical features across these RI strains, including the orderliness by which they space themselves apart within a layer. The population of horizontal cells is one such example, where variation in the orderliness of their patterning maps to two narrow genomic loci. Causal genes and their variants at these loci will be pursued, and comparable spatial statistical analysis will be conducted for the other cell types to map QTL in pursuit of the genetic determinants of neuronal spacing. The consequence of such independent variation in the number of afferent and target neurons upon dendritic differentiation will also be examined, using the AII amacrine cell to explore the unique independent control of its lobular versus dendritic growth. Finally, a role for the transcription factor Sox2 in cholinergic amacrine cells has recently been demonstrated, causing a mis- positioning of these amacrine cells between the inner nuclear layer and ganglion cell layer, and a conversion of their mono-stratifying dendrites into a bi-stratifying morphology. The role of Sox2 will be further explored to identify the downstream genes responsible for these altered cholinergic amacrine cell traits, by transcriptome- profiling of purified cholinergic amacrine cells from Sox2-deficient versus control retinas. The present research proposal will thereby identify the genetic determinants and intercellular interactions that underlie the demographic features of neuronal populations in the retina, clarifying our understanding of retinal development, as well as identifying genetic variants that may contribute to retinal disease.
This research program will identify the genetic determinants controlling the variation in neuron number, laminar positioning and intercellular spacing using the retina as a model system. It will define the cellular interactions and molecular regulation governing neuronal differentiation, including dendritic outgrowth, branching and stratification. These studies will clarify the developmental processes and underlying mechanisms that produce the functional architecture and connectivity of the mature retina. This research will, consequently, contribute to our understanding of developmental disorders of the nervous system, and provide a knowledge base for the emerging field of neural regenerative medicine.
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