The major goal of this proposal is to clarify the molecular events that control the differentiation of sympathetic preganglionic neurons (SPNs) in the developing spinal cord. SPNs are spinal cord visceral motor neurons that innervate the peripheral sympathetic ganglia in circuits to mediate autonomic stress responses. Postmitotic SPN precursors in chick and mouse spinal cords are labeled with an antibody that recognizes active bone morphogenetic protein (BMP) signaling, and normal SPN development is disrupted in a conditional mouse model lacking BMP receptor activity. These observations suggest that this signal is either instructive for SPN fate specification, or required for the execution of the SPN developmental program. This proposal will therefore focus on four aspects of SPN differentiation and its relationship to the BMP signaling pathway. First, the relationship between known markers of SPNs, specific cell lineages in the spinal cord, and the cell population receiving the BMP signal will be defined in transgenic mice. Second, the requirement for BMP signaling in postmitotic differentiation of SPNs and other neuronal populations in the spinal cord will be examined in mouse and chick mutants. Third, the fate of SPN precursors in the conditional mouse model will be determined. Fourth, the mechanism that restricts the usually broad range of BMP signaling to the SPN lineage will be examined. In particular, the consequences to somatic motor neuron development of ectopically-activating BMP signaling pathway components will be assessed in the chick spinal cord. Together, these studies are intended to define the molecular pathway responsible for the postmitotic differentiation of SPNs and for limiting BMP signaling activity to this discrete cell population. These studies will advance our general understanding of spinal cord development, and provide important insight into a critical developmental signaling pathway. Neuronal circuits between SPNs and sympathetic ganglia are required for the efficient function of many organ systems. They can be disrupted following spinal cord injury or in neurodegenerative diseases, including Parkinson's disease. Defining the molecular steps that control SPN development may therefore provide insight into the basis of these disorders and lead to novel strategies for their treatment.
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