The proposed research focuses on the role that neuronal migration may have in the development of neuronal diversity. Specifically, we propose to explore the hypothesis that the phenotypic differences between two closely related subsets of spinal cord cells, somatic motor neurons (SMNs) and autonomic motor neurons (AMNs) arise as a result of signals these cells encounter along their respective migration pathways. Initially, we plan to test hypotheses concerned with mechanisms of AMN migration. By necessity, these hypotheses will be examined in cultured spinal slice preparations that support normal AMN migration. We will seek to determine whether trophic and cell surface interactions play roles in AMN migration. Questions that arise in this regard include: Is AMN migration dependent upon axonal connections with peripheral targets? Do molecules on the surfaces of early developing circumferential axons guide the nonradial migration of AMNs? Do extracellular matrix molecules play a role in AMN movements? Furthermore, we propose to conduct experiments that explore the roles of receptors and intracellular ion levels in AMN movements. For example, questions important to this part of our proposed studies are: Do glutamate receptors gate intracellular changes important to AMN migration? Is this migration dependent on Ca2+ levels? Can intracellular levels of nitric oxide modulate AMN migration? Second in addition to the studies of migratory mechanisms, we will examine the subsequences that AMN migration has for the molecular differentiation of these cells. For instance: Is the characteristic expression of NADPH diaphorase in AMNs triggered by their dorsal migration? Is the motor neuronal, subset-specific expression of neuropeptides related to the migrational differences between SMNs and AMNs? Questions such as these muse be answered because they are important to understanding both normal brain function and degenerative neurological disorders, such as amyotrophic lateral sclerosis (ALS), where differential vulnerability of neuronal populations is a hallmark of the disease process.
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