The relative roles of the Kit receptor in promoting the migration

Vertebrate melanocytes are derived from the neural crest (NC), a population of embryonic precursor cells that arises along the dorsal neural tube then disperses throughout the embryo. In addition to melanocytes, NC cells also contribute to the peripheral nervous system, craniofacial skeleton, heart, endocrine glands, and other tissues and organs (Le Douarin, 1982; Hall and Hörstadius, 1988; Erickson, 1993; Le Douarin et al., 1994; Groves and Bronner-Fraser, 1999). The morphogenesis and differentiation of melanocytes and other NC derivatives requires the transduction of extracellular signals through a variety of cell surface receptors (Weston, 1991; Barsh, 1996; Wehrle-Haller and Weston, 1997; Moellman and Halaban, 1998; Reedy et al., 1998). Among these is the product of the c-kit (kit) gene, a type III receptor tyrosine kinase expressed by melanocytes and melanocyte precursors, or melanoblasts (Qiu et al., 1988; Orr-Urtreger et al., 1990; Motro et al., 1991; Manova and Bachvarova, 1991; Giebel and Spritz, 1991; van der Geer et al., 1994; WehrleHaller and Weston, 1995; Bernex et al., 1996; Opdecamp et al., 1997). In mouse, mutants in Kit (formerly W) are dominant and long have been studied for their effects on the development of melanocytes, as well as hematopoietic precursors and primordial germ cells (PGCs; de Aberle, 1927; Little and Cloudman, 1937; Russell, 1949; Mintz and Russell, 1957; Mayer and Green, 1968; Silvers, 1979; Tan et al., 1990; Nocka et al., 1990; Tsujimura et al., 1991; Giebel and Spritz, 1991; Besmer et al., 1993; Spritz, 1998; Marklund et al., 1998). Mice homozygous for severe Kit alleles lack melanocytes, are deficient in PGCs, and die prenatally or perinatally of macrocytic anemia. Mice that are heterozygous, or homozygous for less severe and viable alleles, completely lack melanocytes or have melanocyte deficiencies, and also may exhibit sterility or impaired fertility, as well as anemia. Similar phenotypes are observed in murine mutants for Steel (Mgf), which encodes the Kit ligand, Steel Factor (SLF; also known as Mast Cell Growth Factor and Stem Cell Factor; Zsebo et al., 1990; Anderson et al., 1990; Huang et al., 1990; Besmer et al., 1993). Despite the long-standing availability of mouse Kit and Steel mutants, questions remain about the roles of these genes in the development of the melanocyte lineage. During normal development in mouse, NC cells leave the dorsal neural tube and shortly thereafter a subpopulation of these cells begins to express Kit as well as early markers of melanocyte differentiation (e.g., the transcription factor Mitf and the melanin synthesis enzyme Dct/Trp2; Steel et al., 1992; WehrleHaller and Weston, 1995; Bernex et al., 1996; MacKenzie et al., 1997; Opdecamp et al., 1997). These melanoblasts then disperse along migratory pathways lined by cells expressing SLF, and ultimately enter the epidermis where they proliferate, colonize hair follicles, and begin to synthesize melanin (Serbedzija et al., 1990; Erickson and Perris, 1993; Wehrle-Haller and Weston, 3425 Development 126, 3425-3436 (1999) Printed in Great Britain © The Company of Biologists Limited 1999 DEV6400