grantor:
University of TorontoThe murine 'W' locus encodes the Kit receptor tyrosine kinase (RTK). Many structural mutations at the 'W' locus, affecting the Kit coding sequence, lead to pleiotropic defects in hematopoiesis, gametogenesis and melanogenesis. Regulatory 'W' mutations, on the other hand, do not affect the Kit coding sequence and cause cell type specific defects. Moreover, the Kit RTK is expressed in several cell types and tissues with no obvious defects in 'W' mutant mice, raising the question of the function of the Kit molecule in these tissues. In this thesis, I have analyzed the molecular basis and developmental defects associated with two spontaneous regulatory mutations in the mouse ' W' locus. I describe the effects of the 'W57' and Wbandedbd mutations on 'Kit' expression during embryogenesis and in the adult animal and show specific defects in melanocyte development in these mutant animals. In addition, I describe the molecular basis of these regulatory 'W' mutations. The Kit RTK is expressed in the adult intestine, but no intestinal defects had been described in 'W' mutant animals. I identify the Kit-expressing cells in the small intestine as the interstitial cells of Cajal (ICC) and demonstrate the importance for this cell type in intestinal pacemaking. Moreover, I analyze the developmental origin and lineage relationships of these Kit-expressing cells in the small intestine and investigate the role of Kit in their development. ICC and smooth muscle cells of the intestine are derived from a common precursor. Moreover, a functional Kit receptor is not required as an instructive signal during lineage determination, but is necessary for ICC proliferation after birth. These results provide novel information on the multiple roles of the Kit RTK in mouse development, as well as new insights into the regulation of expression of this gene.Ph.D
