The long-range goal of this laboratory is to understand the cellular and molecular mechanisms that underlie the development of phenotypic diversity and plasticity in the mammalian peripheral nervous system. To simplify this complex problem we have focused on a particular sublineage of the neural crest, the sympathoadrenal lineage, which gives rise to adrenal medullary chromaffin cells and sympathetic neurons among other derivatives. Adrenal chromaffin cells are phenotypically plastic in that they can convert into sympathetic neurons in response to NGF. This plasticity is of potential medical relevance 1) because of its probable mechanistic relationship to at least some forms of nerve regeneration; and 2) because of the potential utility of using chromaffin cells or cells at earlier stages in the lineage in transplantation therapy for Parkinson's disease.
The specific aims of this application are to I) Study the differentiation of committed embryonic sympathoadrenal progenitor cells in culture using defined populations isolated with specific monoclonal antibodies and fluorescence-activated cell-sorting. The responses of these progenitors to various growth factors and other signals will be analyzed. New progenitor cell lines we have produced may permit us to examine the molecular basis for some of these responses; II & III) Examine the molecular basis of chromaffin cell plasticity in terms of the expression of a neural-specific marker gene, SCG1O. We will explore the use of features of active or potentially-active SCG1O chromatin structure as a molecular marker of plasticity and developmental potential in this lineage. The regulatory elements that control expression of this gene durinq development, chromaffin cell plasticity and regeneration will be studied using transfected cell lines and transgenic mice; IV) Identify the immediate precursor to the committed sympathoadrenal progenitor. An in vitro system has been established in which this postulated """"""""pre-progenitor"""""""" should commit to the sympathoadrenal lineage. we will find monoclonal antibodies that mark this preprogenitor, and make a cell line from this precursor as a first step towards identifyinq molecules involved in the commitment event. A novel """"""""surface-tagging"""""""" approach will ba taken in an attempt to mark this cell, in which a promoter specific to this cell is use to drive the expression of a viral cell surface glycoprotein, in transgenic mice.
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