Recent studies have revolutionized the perception of cilia as an organelle of motility by showing cilia play roles in signaling events that control differentiation and cell growth. This proposal combines genetic, biochemical, molecular and cell biological approaches in order to understand how cilia signal and specify cell fate in the developing spinal cord by studying a protein, ARL13B. Mice deficient for ARL13B have defects in cell specification in the spinal cord due to a function of ARL13B in cilia. The proposed experiments in Aim 1 will genetically determine if ARL13B acts in the established signaling pathways that initially specify neural cell fate.
Aim 2 will define how and when ARL13B is required in the neural progenitor cells that develop as motor neurons and subsequently as oligodendrocytes. The goal of Aim 3 is to relate the function of ARL13B in cell fate specification to its function in cilia by defining the functional domains that regulate ARL13B localization and by identifying interacting proteins. Taken together these results will provide new understanding of the role of cilia proteins in cell specification. The fundamental role ciliary proteins play in basic cellular functions is underscored by the diverse spectrum of phenotypes exhibited by patients with defects in these proteins. Obesity, situs inversus, infertility, diabetes, polydactyly, renal dysfunction, learning disabilities, epilepsy, deafness, anosmia and blindness are all seen in patients with defective cilia and are thought to result from failures in the formation, motility and signaling ability of cilia. By establishing the mechanism through which ARL13B functions in ciliogenesis and connecting it to the role of ARL13B in signaling to specify spinal cord cell fates the proposed work will provide a better understanding of motor neuron and oligodendrocyte development that can impact the treatment of dysmyelinating diseases such as multiple sclerosis as well as spinal cord injury. Given the direct connections between the signaling pathways that govern cell choice and the human disease states in which the same pathways are disrupted, this proposed work has high potential to improve human health
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