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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG009686-15
Application #
7022280
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Chen, Wen G
Project Start
1991-02-01
Project End
2008-02-28
Budget Start
2006-03-15
Budget End
2008-02-28
Support Year
15
Fiscal Year
2006
Total Cost
$425,415
Indirect Cost
Name
Winifred Masterson Burke Med Research Institute
Department
Type
DUNS #
780676131
City
White Plains
State
NY
Country
United States
Zip Code
10605
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Sasaki, Hayato; Berlin, Roseann; Baker, Harriet (2004) Transient expression of tyrosine hydroxylase promoter/reporter gene constructs in the olfactory epithelium of transgenic mice. J Neurocytol 33:681-92
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Baker, Harriet; Kobayashi, Kazuto; Okano, Hideyuki et al. (2003) Cortical and striatal expression of tyrosine hydroxylase mRNA in neonatal and adult mice. Cell Mol Neurobiol 23:507-18
Saino-Saito, Sachiko; Berlin, Roseann; Baker, Harriet (2003) Dlx-1 and Dlx-2 expression in the adult mouse brain: relationship to dopaminergic phenotypic regulation. J Comp Neurol 461:18-30
Moon, Young Wha; Baker, Harriet (2002) Lectin-induced apoptosis of mature olfactory receptor cells. J Neurosci Res 68:398-405

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