THE KIT-LIGAND (STEEL FACTOR) AND ITS RECEPTOR C-KIT W - PLEIOTROPIC ROLES IN GAMETOGENESIS AND MELANOGENESIS/

The c-kit receptor tyrosine kinase belongs to the PDGF/CSF-1/c-kit rec eptor subfamily. The kit-ligand, KL, also called steel factor, is synt hesized from two alternatively spliced mRNAs as transmembrane proteins that can either be proteolytically cleaved to produce soluble forms o f KL or can function as cell-associated molecules. The c-kit receptor kinase and KL are encoded at the white spotting (W) and steel (Sl) loc i of the mouse, respectively. Mutations at both the W and the Sl locus cause deficiencies in gametogenesis, melanogenesis and hematopoiesis. The c-kit receptor is expressed in the cellular targets of W and Sl m utations, while KL is expressed in their microenvironment. In melanoge nesis, c-kit is expressed in melanoblasts from the time they leave the neural crest and expression continues during embryonic development an d in the melanocytes of postnatal animals. In gametogenesis c-kit is e xpressed in primordial germ cells, in spermatogonia, and in primordial and growing oocytes, implying a role at three distinct stages of game togenesis. Many mutant alleles are known at W and Sl loci and their ph enotypes vary in the degree of severity in the different cellular targ ets of the mutations. While many TV and Sl alleles severely affect pri mordial germ cells (PGC), several mild Sl alleles have weak effects on PGCs and exhibit differential male or female sterility. Steel Panda ( Sl(pan)) is a KL expression mutation in which KL RNA transcript levels are reduced in most tissues analyzed. In female Sl(pan)/Sl(pan) mice, ovarian follicle development is arrested at the one layered cuboidal stage as a result of reduced KL expression in follicle cells, indicati ng a role for c-kit in oocyte growth. W-sh is a c-kit expression mutat ion, which affects mast cells and melanogenesis. While the mast cell d efect results from lack of c-kit expression, the pigmentation deficien cy appears to stem from ectopic c-kit receptor expression in the somit ic dermatome at the time of migration of melanoblasts from the neural crest to the periphery. It is proposed that the ectopic c-kit expressi on in W-sh mice affects early melanogenesis in a dominant fashion. The ''sash'' or white belt of W-sh/+ animals and some other mutant mice i s explained by the varying density of melanoblasts along the body axis of wild-type embryos.