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Review: Melanocyte Migration and Survival Controlled by SCF/c-kit Expression

2001; Elsevier BV; Volume: 6; Issue: 1 Linguagem: Inglês

10.1046/j.0022-202x.2001.00006.x

1529-1774

Hisahiro Yoshida, Grimm Thomas, Emi K. Nishimura, Eri Nishioka, Shin‐Ichi Nishikawa, Takahiro Kunisada,

Biochemical Analysis and Sensing Techniques

Melanocytes are derived from neural crest and migrate along the dorsolateral pathway to colonize the final destination in the skin. Stem cell factor and its receptor c-kit were identified as gene products of Sl and W mutant loci; both of them were known to have defects in melanocytes survival. In this review, we focus on the function of stem cell factor and c-kit in melanocyte migration and survival, which has become clearer in the last decade. By analysis of both molecules in wild-type and white spotting mutant mice, ligand and receptor set were shown to play multiple roles in the development of melanocytes in mouse ontogeny. Functional blockade of c-kit by specific monoclonal antibody illustrated distinct c-kit dependent and independent stages in melanocyte development. Finally, SCF transgene expression demonstrated that part of the c-kit dependent step is regulated by spatiotemporally specific ligand expression and also indicated the presence of c-kit independent melanocyte stem cells in postnatal skin. Melanocytes are derived from neural crest and migrate along the dorsolateral pathway to colonize the final destination in the skin. Stem cell factor and its receptor c-kit were identified as gene products of Sl and W mutant loci; both of them were known to have defects in melanocytes survival. In this review, we focus on the function of stem cell factor and c-kit in melanocyte migration and survival, which has become clearer in the last decade. By analysis of both molecules in wild-type and white spotting mutant mice, ligand and receptor set were shown to play multiple roles in the development of melanocytes in mouse ontogeny. Functional blockade of c-kit by specific monoclonal antibody illustrated distinct c-kit dependent and independent stages in melanocyte development. Finally, SCF transgene expression demonstrated that part of the c-kit dependent step is regulated by spatiotemporally specific ligand expression and also indicated the presence of c-kit independent melanocyte stem cells in postnatal skin. melanocyte human cytokeratin 14 platelet derived growth factor stem cell factor transgenic monoclonal antibody Melanocytes (MC) originate from the neural crest and migrate along the dorsolateral pathway to colonize their final destination, the skin epidermal basal layer or hair follicles. From the various coat color pigmentation patterns found in many animal species, it was obvious that MC migration and/or survival in the periphery is affected by genetic or environmental differences during development. During the last decade, several molecules indispensable for MC development were identified as gene products encoded by coat color mutant loci. We would like to review the function of those molecules, with specific reference to stem cell factor (SCF) and its receptor c-kit in MC migration and survival. Due to the absence of useful MC markers, it was difficult to describe the migration of MC during mice embryogenesis. Jackson et al reported the specific expression of DOPAchrome tautomerase (DT) in a MC population and described the distribution pattern of MC in embryogenesis (Steel et al., 1992Steel K.P. Davidson D.R. Jackson I.J. TRP-2/DT, a new early melanoblast marker, shows that steel growth factor (c-kit ligand) is a survival factor.Development. 1992; 115: 1111-1119Crossref PubMed Google Scholar), and made a useful mouse model harboring the α-galactosidase gene under the control of the DT promoter region (Cable et al., 1995Cable J. Jackson I.J. Steel K.P. Mutations at the W locus affect survival of neural crest-derived melanocytes in the mouse.Mech Dev. 1995; 50: 139-150Crossref PubMed Scopus (113) Google Scholar).Wehrle-Haller and Weston, 1995Wehrle-Haller B. Weston J.A. Soluble and cell-bound forms of steel factor activity play distinct roles in melanocyte precursor dispersal and survival on the lateral neural crest migration pathway.Development. 1995; 121: 731-742PubMed Google Scholar and our group (Kunisada et al., 1996Kunisada T. Yoshida H. Ogawa M. Shultz L.D. Nishikawa S.I. Characterization and isolation of melanocyte progenitors from mouse embryos.Dev Growth Differ. 1996; 38: 87-97Crossref Scopus (27) Google Scholar;Yoshida et al., 1996aYoshida H. Kunisada T. Kusakabe M. Nishikawa S. Nishikawa S.I. Distinct stages of melanocyte differentiation revealed by analysis of non-uniform pigmentation patterns.Development. 1996; 122: 1207-1214PubMed Google Scholar) independently detected MC distribution during development using c-kit as a specific marker for MC. As shown in Figure 1, the earliest MC population was detected in the dorsal region of the hindbrain at 9.5–10.0 dpc. Many MC were detected from the dorsal region from the hindbrain to the root of the tail bud by 10.5 dpc. MC gradually proliferate and migrate through the dermis horizontally to the ventral region, and then invade into the epidermis between 12.5 and 14.0 dpc. Epidermal MC also expand in number and migrate through the epidermal basal layer between 13.0 and 15.5 dpc (Yoshida et al., 1996aYoshida H. Kunisada T. Kusakabe M. Nishikawa S. Nishikawa S.I. Distinct stages of melanocyte differentiation revealed by analysis of non-uniform pigmentation patterns.Development. 1996; 122: 1207-1214PubMed Google Scholar). This MC distribution pattern is clearly demonstrated in the coat color of KitW./+ or MitfMiWh/+, which show white spot formation in the belly and/or blaze, these are the last regions to be colonized by MC during development (see Figure 1, top, 13.5–14.5 dpc embryo). These results suggest that the number of MC in these mutant mice is smaller than with wild-type mice, though the migration pattern itself is basically unaffected. Analysis of c-kit expression and MC distribution in the "spotting" mutant mice suggested the function of the molecules encoded at these mutant loci. MC number in the lethal spotting (edn3ls/edn3ls;Hosoda et al., 1994Hosoda K. Hammer R.E. Richardson J.A. Baynash A.G. Cheung J. Giaid C. Yanagisawa M. Targeted and natural (Piebald-Lethal) mutations of endothelin-b receptor gene produce megacolon associated with spotted coat color in mice.Cell. 1994; 79: 1267-1276Abstract Full Text PDF PubMed Scopus (854) Google Scholar) mutant is very small prior to entry into the epidermis, indicating that endothelin-3 is an indispensable factor for MC proliferation during dermal migration (Yoshida et al., 1996aYoshida H. Kunisada T. Kusakabe M. Nishikawa S. Nishikawa S.I. Distinct stages of melanocyte differentiation revealed by analysis of non-uniform pigmentation patterns.Development. 1996; 122: 1207-1214PubMed Google Scholar). Transgenic rescue of this mutant also suggested that endothelin-3 plays a pivotal role around day 11 dpc to 12 dpc when MC migrate through the dermis (Shin et al., 1999Shin M.K. Levorse J.M. Tilghman S.M. The temporal requirement for endothelin receptor-B signaling during neural crest development.Nature. 1999; 402: 496-501Crossref PubMed Scopus (285) Google Scholar). Coat color spotting patterns of this mutant resemble the distribution patterns of day 10 dpc embryos (Figure 1;Yoshida et al., 1996aYoshida H. Kunisada T. Kusakabe M. Nishikawa S. Nishikawa S.I. Distinct stages of melanocyte differentiation revealed by analysis of non-uniform pigmentation patterns.Development. 1996; 122: 1207-1214PubMed Google Scholar). In contrast, there are several unique mutants with patchy white spots that are different to the MC distribution patterns of the embryo. From genetic analysis, several independent coat color mutation loci, W (=Kit), Ph or Rw, were mapped to a tiny region on chromosome 5 (Silvers, 1979Silvers N.K. The Coat Colors of Mice: A Model for Mammalian Gene Action and Interaction. New York, Springer-Verlag1979Crossref Google Scholar). Ph/+ mice have a large white spot covering the whole trunk. As the Ph mutation is a deletion including the PDGF receptor α gene, this mutant has several defects in the neural crest derived cell lineages (Stephenson et al., 1991Stephenson D.A. Mercola M. Anderson E. Wang C. Stiles C.D. Bowen-Pope D.F. Chapman V.M. Platelet-derived growth factor receptor α-subunit gene (pdgfra) is deleted in the mouse patch (Ph) mutation.Proc Natl Acad Sci USA. 1991; 88: 6-10Crossref PubMed Scopus (156) Google Scholar;Morrison-Graham et al., 1992Morrison-Graham K. Schatteman G.C. Weston J.A. A PDGF receptor mutation in the mouse (Patch) perturbs the development of a non-neuronal subset of neural crest-derived cells.Development. 1992; 115: 133-142Crossref PubMed Google Scholar). The MC defect observed in the PdgfraPh mutant was thought at first to result from this receptor defect; however, pigmented MC were detectable in the PdgfraPh/PdgfraPh mutant (Yoshida, unpublished observation). Furthermore, MC of wild-type mice do not express PDGF receptor α, and no effect on development was observed after the administration of a monoclonal antibody (MoAb) that blocks PDGF receptor α function (Takakura et al., 1996Takakura N. Yoshida H. Kunisada T. Nishikawa S.I. A novel function of platelet derived growth factor receptor alpha: its transient expression in the epidermis is essential for hair canal formation.J Invest Dermatol. 1996; 107: 770-777Crossref PubMed Scopus (75) Google Scholar) or in vitro cultured MC (Yoshida, unpublished observation). The analysis of c-kit expression patterns in this mutant during development unmasked the mechanism of spotting formation. The MC distribution in Ph/+ mice at their early gestational stages is not different from those of wild-type mice (Figure 1, middle); however, aberrant expression of c-kit in the mesenchymal cells was found in unpigmented regions and MC gradually disappeared from this region (Wehrle-Haller et al., 1996Wehrle-Haller B. Morrison-Graham K. Weston J.A. Ectopic c-kit expression affects the fate of melanocyte precursors in Patch mutant embryos.Dev Biol. 1996; 177 (10.1006/dbio.1996.0178): 463-474Crossref PubMed Scopus (45) Google Scholar). Ectopic expression of c-kit by mesenchymal cells may deplete local SCF resulting in ligand starvation-induced MC apoptosis. This idea was originally presented byDuttlinger et al., 1993Duttlinger R. Manova K. Besmer P. W-sash affects positive and negative elements controlling c-kit expression: ectopic c-kit expression at sites of kit-ligand expression affects melanogenesis.Development. 1993; 118: 705-717PubMed Google Scholar in the analysis of the KitWsh/+ mutant spotting pattern formation. Like these mutant mice, Rw/+ mice also have a rump region specific white spot (Silvers, 1979Silvers N.K. The Coat Colors of Mice: A Model for Mammalian Gene Action and Interaction. New York, Springer-Verlag1979Crossref Google Scholar), and this mutation also has the chromosomal rearrangement near the c-kit gene (Nagle et al., 1994Nagle D.L. Martin-DeLeon P. Hough R.B. Buc'An M. Structural analysis of chromosomal rearrangements associated with the developmental mutations Ph, W19H, and Rw on mouse chromosome 5.Proc Natl Acad Sci USA. 1994; 91: 7237-7241Crossref PubMed Scopus (42) Google Scholar). MC number and distribution pattern of Rw/+ mutants were comparable with the wild-type mice, but MC gradually disappeared from the mesenchymal region with aberrant expression of c-kit (Figure 1, bottom; Figure 2c). As shown in Figure 2(a), SCF is expressed in the dermo-myotome of 10–11 dpc embryo where c-kit-expressing MC migrate along to the periphery (Figure 2c). Similar observations of MC migration in this mutant were reported recently (Jordan and Jackson, 2000Jordan S.A. Jackson I.J. A late wave of melanoblast differentiation and rostrocaudal migration revealed in patch and rump-white embryos.Mech Dev. 2000; 92 (10.1016/s0925-4773(99)00332-9): 135-143Crossref PubMed Scopus (27) Google Scholar). These findings suggested that the rump spotting of Rw/+ mutants resulted from a similar mechanism to KitWsh/+ and PdgfraPh/+ mutants. In contrast, aberrant expression of SCF does not induce a white spot. Because of transcriptional defects, MGFSlcon/MGFSlcon mutant mice express SCF in some ectopic regions such as the reproductive tract, genitalia, lip, or nipples (Beechey and Searle, 1983Beechey B.C.V. Searle A.G. Contrasted, a steel allele in the mouse with intermediate effects.Genet Res Com. 1983; 42: 183-191Crossref PubMed Scopus (11) Google Scholar). Those ectopic SCF expressions induce the migration, proliferation, and survival of MC outside of hair follicles or the epidermis (Bedell et al., 1995Bedell M.A. Brannan C.I. Evans E.P. Copeland N.G. Jenkins N.A. Donovan P.J. DNA rearrangements located over 100 kb 5′ of the Steel (Sl)-coding region in Steel-panda and Steel-contrasted mice deregulate Sl expression and cause female sterility by disrupting ovarian follicle development.Genes Dev. 1995; 9: 455-470Crossref PubMed Scopus (129) Google Scholar). This mutant phenotype suggests that MC migration and survival is finely controlled by SCF and c-kit expression during embryogenesis. An epigenetic approach is required in order to investigate the function of SCF and c-kit in each MC developing step, as SCF and c-kit defective mutants die perinatally and their MC development is affected at an earlier stage. We have established the c-kit blocking MoAb ACK2 and analyzed MC development by injecting this antibody in to the wild-type mice at various stages of development (Nishikawa et al., 1991Nishikawa S. Kusakabe M. Yoshinaga K. et al.In utero manipulation of coat color formation by a monoclonal anti-c-kit antibody: Two distinct waves of c-kit-dependency during melanocyte development.EMBO J. 1991; 10: 2111-2118Crossref PubMed Scopus (394) Google Scholar;Yoshida et al., 1993Yoshida H. Nishikawa S.I. Okamura H. Sakakura T. Kusakabe M. The role of c-kit proto-oncogene during melanocyte development in mouse. in vivo approach by the in utero microinjection of anti-c-kit antibody.Dev Growth Differ. 1993; 35: 209-220Crossref Scopus (39) Google Scholar;Okura et al., 1995Okura M. Maeda H. Nishikawa S. Mizoguchi M. Effects of monoclonal anti-c-kit antibody (ACK2) on melanocytes in newborn mice.J Invest Dermatol. 1995; 105: 322-328Crossref PubMed Scopus (65) Google Scholar;Yoshida et al., 1996aYoshida H. Kunisada T. Kusakabe M. Nishikawa S. Nishikawa S.I. Distinct stages of melanocyte differentiation revealed by analysis of non-uniform pigmentation patterns.Development. 1996; 122: 1207-1214PubMed Google Scholar). As the removal of SCF and the addition of ACK2 both induced apoptosis of MC (Okura et al., 1995Okura M. Maeda H. Nishikawa S. Mizoguchi M. Effects of monoclonal anti-c-kit antibody (ACK2) on melanocytes in newborn mice.J Invest Dermatol. 1995; 105: 322-328Crossref PubMed Scopus (65) Google Scholar;Ito et al., 1999Ito M. Kawa Y. Ono H. et al.Removal of stem cell factor or addition of monoclonal anti-c-kit antibody induces apoptosis in murine melanocyte precursors.J Invest Dermatol. 1999; 112: 796-801Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar), this strategy can establish the SCF defective state at any developmental stage. Using this MoAb injection technique, we found that SCF and c-kit interaction is required for (i) survival of MC during migration in the dermis, (ii) survival of MC in the epidermal sheet prior to entering the hair follicles, and (iii) survival of MC proliferating in the anagen hair follicles. These results indicate that MC have distinct SCF/c-kit dependent or independent developmental stages, in contrast to the continuous expression of c-kit on the MC surface during embryogenesis. It is interesting question as to what regulates the c-kit dependency of MC. There are several reports that describe the expression patterns of SCF and c-kit in numerous organs including the skin (Manova and Bachvarova, 1991Manova K. Bachvarova R.F. Expression of c-kit encoded at the W locus of mice in developing embryonic germ cells and presumptive melanoblasts.Dev Biol. 1991; 146: 312-324Crossref PubMed Scopus (194) Google Scholar;Motro et al., 1991Motro B. Kooy D.V.D. Rossant J. Contiguous patterns of c-kit and steel expression: analysis of mutations at the W and Sl loci.Development. 1991; 113: 1207-1221PubMed Google Scholar;Besmer et al., 1993Besmer P. Manova K. Duttlinger R. Huang E.J. Packer A. Gyssler C. Bachvarova R. The kit-ligand (steel factor) and its receptor c-kit/W: pleiotropic roles in gametogenesis and melanogenesis.Development. 1993; 119: 125-137Google Scholar), but the signal:noise ratio of those studies is not satisfactory to detect distinct cells expressing SCF in skin tissues. We tried to detect the SCF protein expression using several antibodies by means of whole-mount immunostaining, and succeeded in detecting its expression in skin tissues. As shown in Figure 3(a), SCF is expressed in the epidermal basal layer and the whole hair follicle keratinocyte of 15 dpc mice. Compatible with the expression pattern of its ligand, c-kit immunoreactive MC are located in the epidermal basal layer and whole hair follicles at this stage (Figure 3c). After birth, murine MC gradually disappear from the epidermal basal layer (Hirobe, 1984Hirobe T. Histochemical survey of the distribution of the epidermal melanoblasts and melanocytes in the mouse during fetal and postnatal periods.Anat Rec. 1984; 208: 589-594Crossref PubMed Scopus (110) Google Scholar). In accordance with this observation, the expression of SCF in the interfollicular epidermal layer decreases after hair follicle formation, and is restricted to the hair matrix epidermis in juvenile mice skin (Figure 3c), where the c-kit expressing MC proliferate and produce pigment granules (Figure 3c). Although these results appeared to contradict our previous report demonstrating the ability of the SCF gene promoter region to express transgene in dermal papilla during embryogenesis (Yoshida et al., 1996bYoshida H. Hayashi S.I. Shultz L.D. Yamamura K.I. Nishikawa S. Nishikawa S.I. Kunisada T. Neural and skin specific expression pattern conferred by Steel factor regulatory sequence in transgenic mice.Dev Dyn. 1996; 207 (10.1002/(sici)1097-0177(199610)207:2>222::aid-aja10>3.3.co;2-d): 222-232Crossref PubMed Scopus (46) Google Scholar), low level SCF expression in embryonic dermal papilla was also detected by immunostaining (Figure 3c, asterisk). The difference between these two studies suggests that the enhancer domain that regulates epidermal SCF expression resides outside of the 10 kbp that we have studied (Yoshida et al., 1996bYoshida H. Hayashi S.I. Shultz L.D. Yamamura K.I. Nishikawa S. Nishikawa S.I. Kunisada T. Neural and skin specific expression pattern conferred by Steel factor regulatory sequence in transgenic mice.Dev Dyn. 1996; 207 (10.1002/(sici)1097-0177(199610)207:2>222::aid-aja10>3.3.co;2-d): 222-232Crossref PubMed Scopus (46) Google Scholar). These results clearly indicate the importance of SCF and c-kit interaction in the whole process of MC migration and differentiation in mice ontogeny. Contiguous expression patterns of this ligand and the receptor are also observed in the other organs (Figure 2c, b), suggesting this ligand/receptor signal transduction is regulated by the local expression but not by systematic circulation of the soluble ligand (data not shown). In humans and mammals such as dogs, horses, etc., skin MC reside in both the hair follicle and the epidermal basal layer. In contrast, most laboratory mice have no epidermal MC in hairy skin. What mechanism regulates MC residency in distinct regions of the skin between these species? Since epidermal and hair follicle MC express different cadherins on their surface (Nishimura et al., 1999Nishimura E.K. Yoshida H. Kunisada T. et al.Regulation of E- and P-cadherin expression correlated with melanocyte migration and diversification.Dev Biol. 1999; 215 (10.1006/dbio.1999.9478): 155-166Crossref PubMed Scopus (89) Google Scholar), the difference may be detected in each MC population as an intrinsic mechanism. This suggested that the environment of human but not murine epidermal basal layers has the ability to support MC survival. To confirm this idea, we made a transgenic mice that expresses SCF under the control of the human cytokeratin 14 (hK14) gene promoter, which was reported to express transgene in the epidermal basal layer (Byrne et al., 1994Byrne C. Tainsky M. Fuchs E. Programming gene expression in developing epidermis.Development. 1994; 120: 2369-2383Crossref PubMed Google Scholar). SCF transgene (Tg) expression allowed MC survival and development in the epidermal basal layer in mouse hairy skin (Figure 4;Kunisada et al., 1998aKunisada T. Lu S.Z. Yoshida H. et al.Murine cutaneous mastocytosis and epidermal melanocytosis induced by keratinocyte expression of transgenic stem cell factor.J Exp Med. 1998; 10: 1565-1573Crossref Scopus (159) Google Scholar,Kunisada et al., 1998bKunisada T. Yoshida H. Yamazaki H. et al.Transgene expression of steel factor in the basal layer of epidermis promotes survival, proliferation, differentiation and migration of melanocyte precursors.Development. 1998; 125: 2915-2923PubMed Google Scholar). Epidermal MC survival was dependent on SCF/c-kit interactions and was abolished by anti-c-kit MoAb injection. Local ligand expression therefore appears to regulate the requirement for c-kit in MC survival (Kunisada et al., 1998bKunisada T. Yoshida H. Yamazaki H. et al.Transgene expression of steel factor in the basal layer of epidermis promotes survival, proliferation, differentiation and migration of melanocyte precursors.Development. 1998; 125: 2915-2923PubMed Google Scholar). MC in the epidermis can proliferate and enter MC free regions during late gestational stages (Yoshida et al., 1996aYoshida H. Kunisada T. Kusakabe M. Nishikawa S. Nishikawa S.I. Distinct stages of melanocyte differentiation revealed by analysis of non-uniform pigmentation patterns.Development. 1996; 122: 1207-1214PubMed Google Scholar). In addition, it appeared as if this proliferation was restricted by the contact inhibition between MC, as MC do not proliferate extensively in wild-type mice during late gestation, and the concentration in the fully MC filled region is constant during those stages (Yoshida, unpublished observation). These results supported the idea that MC can proliferate and expand their residing area if the appropriate conditions are established. This phenomenon was actually observed in hK14-SCF Tg mice. This transgenic mice epidermis can be depigmented by anti-c-kit antibody injection, but a few days later, tiny-pigmented spots are found that gradually expand in size and cover the whole skin with pigmentation (Kunisada et al., 1998bKunisada T. Yoshida H. Yamazaki H. et al.Transgene expression of steel factor in the basal layer of epidermis promotes survival, proliferation, differentiation and migration of melanocyte precursors.Development. 1998; 125: 2915-2923PubMed Google Scholar). This result suggests that even after birth, MC can migrate through the epidermal basal layer. This result also indicates that there must be a MC stem cell population that can survive independent of c-kit signal transduction. As there are always a single or a few pigmented hair follicles found in these tiny-pigmented spots (Figure 5), these c-kit-independent MC stem cells may reside in the hair follicles and migrate outside of the follicles in a c-kit-dependent manner. The location of the niche with the hair follicle where MC stem cells reside is an intriguing question. As mentioned above, SCF is expressed in tissues through which MC migrate. As the SCF trans-membrane region defective mutant MgfSld/MgfSld mice have no coat color pigmentation, MC seem to require membrane-bound SCF for their migration and survival. The fact that the phenotype was detected in soluble-form SCF transgenic mice (Kunisada et al., 1998bKunisada T. Yoshida H. Yamazaki H. et al.Transgene expression of steel factor in the basal layer of epidermis promotes survival, proliferation, differentiation and migration of melanocyte precursors.Development. 1998; 125: 2915-2923PubMed Google Scholar) confirmed that only membrane-bound form SCF is necessary for MC survival. In contrast, small numbers of MC survive and migrate to the periphery until 12.5 dpc in MgfSld/MgfSld mice (Grimm, unpublished observation). In addition, SCF-defective MgfSl/MgfSl mutant MC development was supported by soluble SCF addition in an in vitro culture system (Ito et al., 1999Ito M. Kawa Y. Ono H. et al.Removal of stem cell factor or addition of monoclonal anti-c-kit antibody induces apoptosis in murine melanocyte precursors.J Invest Dermatol. 1999; 112: 796-801Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). In order to know whether only the membrane-bound form of SCF is required for MC migration and survival in skin tissue, we mated MgfSld/MgfSld mutant mice with hK14-SCF Tg mice. As this transgenic mutant has both membrane-bound and soluble forms of SCF in the epidermal basal layer, but only the endogenous soluble form of SCF in hair follicles, we expected to observe the functional difference between membrane-bound and soluble-form SCF on MC development between interfollicular epidermal MC and follicular MC. Interestingly, this combination resulted in mice with patchy pigmented skin with unpigmented fur covering the whole body (Yoshida, unpublished observation). There are several possibilities to explain this phenotype. MC may require the membrane-bound form of SCF for their survival, or for their migration from the epidermis to the hair follicle, or for differentiation to produce pigment granules. Each possibility is now under investigation. For MC survival and migration, spatiotemporally regulated expression of membrane-bound SCF and signal transduction through c-kit receptor tyrosine kinase is a key event at several stages of MC development. On the other hand, the analysis of its function in MC development also demonstrated the presence of c-kit-independent MC survival, especially at the stem cell stage in postnatal skin. Close investigation of this ligand and receptor signal transduction system will be helpful for understanding common mechanisms in cell survival and migration.