Very few neuronal cell lines exhibit differentiated properties of mature neurons. Most existing lines are immature and neuroblast-like, which limits their usefulness. Often the identity of the parental cell type from which the lines arose is unknown. We propose to derive cultured cell lines of catecholaminergic neurons or adrenal medullary cells from tissues of transgenic (TG) mice in which oncogenes are expressed from the rat tyrosine hydroxylase (TH) promoter. Initially we will determine which regulatory elements are necessary for cell specific expression of tyrosine hydroxylase in transgenic mice using both oncogene and non-oncogene reporter genes. We are particularly interested in determining if different TH expressing cells (CNS vs PNS or dopaminergic vs noradrenergic CNS neurons) require different enhancer elements. Transgenic animals will be generated with the appropriate TH enhancer-oncogene constructs and catecholaminergic tissues from oncogene-expressing animals will be cultured. Cell lines will be selected and characterized for a variety of neuronal specific traits. If necessary animals bearing several different oncogenes will be breed to increase the efficiency of immortalization. Lastly, TH+ cells will be ablated during development by targeting the expression of the diphtheria toxin gene or the Herpes simplex virus thymidine kinase gene to catecholaminergic cells in transgenic mice.
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