Conditional Deletion of Kit in Melanocytes: White Spotting Phenotype Is Cell Autonomous.
It is well established that cell-intrinsic signaling through the receptor tyrosine kinase KIT is critical for the development of neural crest-derived melanocytes. Nevertheless, it is not entirely clear whether Kit acts exclusively in a melanocyte-autonomous manner or in addition indirectly through other cell types. To address this question in vivo, we generated a targeted allele of Kit that allowed for CRE recombinase-mediated deletion of the transmembrane domain of KIT. Mice carrying one copy of the targeted allele and expressing CRE under the melanoblast/melanocyte-specific tyrosinase promoter exhibited a white spotting phenotype that was even more extensive compared with that found in mice heterozygous for a Kit-null allele. This phenotype is unlikely the result of sequestration of KIT ligand by neighboring cells or by potentially secreted forms of KIT because the spotting phenotype could not be rescued by overexpression of KITL. Likewise, overexpression of endothelin-3 or hepatocyte growth factor was unable to rescue melanocytes in these mice. Although the severity of the observed phenotype remains to be explained, the findings indicate that melanocyte-selective impairment of Kit is sufficient to interfere with normal melanocyte development.
Department of Tissue and Organ Development, Gifu University Graduate School of Medicine, Gifu, Japan.
Hitomi
H
Aoki
Department of Tumor Pathology, Regeneration, and Advanced Medical Science, Gifu University Graduate School of Medicine, Gifu, Japan.
Hiroyuki
H
Tomita
Department of Tumor Pathology, Regeneration, and Advanced Medical Science, Gifu University Graduate School of Medicine, Gifu, Japan.
Akira
A
Hara
Department of Tissue and Organ Development, Gifu University Graduate School of Medicine, Gifu, Japan. Electronic address: tkunisad@gifu-u.ac.jp.
Takahiro
T
Kunisada
D000483:Alleles; D000818:Animals; D001331:Automation; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D019334:Endothelin-3 / Q000235:genetics*; D000078404:Epidermal Cells; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D007150:Immunohistochemistry; D008544:Melanocytes / Q000166:cytology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011897:Random Allocation; D012680:Sensitivity and Specificity; D017384:Sequence Deletion; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000235:genetics; D015854:Up-Regulation
D019334:Endothelin-3; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit