Elucidating the mechanisms that determine neuronal phenotype during development and that regulate gene expression in adults is a key issue in neurobiology. Understanding these phenomena in dopaminergic (DA) neurons has been the focus of much research because of their loss in the substantia nigra pars compacta in Parkinson's disease (PD). The olfactory bulb (OB) contains a population of periglomerular (PG) DA neurons with characteristics that provide both an ideal model for understanding regulation of DA phenotypic expression and a potential source of cells for transplantation. OB DA neurons are derived throughout life from stem cells in the anterior subventricular zone (SVZa) and migrate in the rostral migratory stream to the OB. Data from a transgenic mouse produced in our laboratory, expressing a lacZ reporter gene driven by a 9kb tyrosine hydroxylase (TH) promoter suggest the testable hypothesis that OB DA precursors are phenotypically committed before they migrate to their final position in the glomerular layer but that full DA expression requires environmental cues during progenitor cell migration.
Two specific aims will test this hypothesis.
Aim 1 will characterize expression of molecules associated with DA phenotypic differentiation in developing and adult animals as well as signaling pathways involved in TH expression.
Aim 1 also will employ in vivo tracer injections and slice cultures to investigate mechanisms regulating proliferation and migration of DA neurons.
Aim 2 will employ primary cultures of neonatal OB taken from the lacZ expressing transgenic mice to delineate signal transduction pathways required for differentiation of DA neurons and regulation of TH expression.
Aim 2 will use a newly characterized OB clonal cell line derived from mice expressing SV4OT-antigen (ts) directed by the 9kb TH promoter to study molecular mechanisms involved in DA differentiation. The proposed aims will delineate the molecular mechanisms underlying differentiation of SVZa stem cells into DA neurons. Understanding pathways involved in differentiation and regulation of OB DA neurons is necessary to establishing their potential for transplants in PD patients.
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