title: Cooperative and indispensable roles of endothelin 3 and KIT signalings in melanocyte development.
abstract: The development of melanocytes from neural crest-derived precursor cells depends on signaling by the receptor tyrosine kinase KIT and the G protein-coupled endothelin receptor B (EDNRB) pathways. Loss-of-function mutations in either of these two signaling receptor molecules cause a loss or a marked reduction in the number of melanocyte precursors in the embryo and finally lead to loss of the coat color. Using cultures of embryonic stem (ES) cells to induce melanocyte differentiation in vitro, we investigated the requirement for EDNRB signaling during the entire developmental process of the melanocyte, in association with that for KIT signaling. During the 21-day period necessary for the induction of mature melanocytes from undifferentiated ES cells, endothelin 3 (EDN3), a ligand for EDNRB, increased the number of melanocytes in proportion to the period during which it was present. We tested the compensatory effect of EDNRB signaling on KIT signaling in vivo by using Kit(W-LacZ)/Kit(W-LacZ) ES cells and confirmed that the ectopic expression of EDN3 in the skin reduced the white spotting of Kit(W57)/Kit(W57)mice. KIT ligand (KITL) and EDN3 worked synergistically to induce melanocyte differentiation in vitro; however, the complete lack of EDNRB signaling attained by the use of EDN3-/- ES cells and an EDNRB antagonist, BQ788, revealed that the resulting failure of melanocyte development was not compensated by the further activation of KIT signaling by adding KITL. Simultaneous blockade of EDNRB and KIT signalings eliminated melanocyte precursors completely, suggesting that the maintenance or survival of early melanocyte precursors at least required the existence of either EDNRB or KIT signalings.
authors.affiliation: Department of Tissue and Organ Development, Regeneration and Advanced Medical Science, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Aoki
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Motohashi
authors.forename: Naoko
authors.initials: N
authors.lastname: Yoshimura
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yamane
authors.forename: J J
authors.initials: JJ
authors.lastname: Panthier
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kunisada
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D019334:Endothelin-3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013997:Time Factors
chemical_list: D019334:Endothelin-3; C509804:Gpr37 protein, mouse; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; D019089:Stem Cell Factor; D017228:Hepatocyte Growth Factor; D019009:Proto-Oncogene Proteins c-kit