W-sash affects positive and negative elements controlling c-kit expression: ectopic c-kit expression at sites of kit-ligand expression affects melanogenesis.
The receptor tyrosine kinase c-kit and its cognate ligand KL are encoded at the white spotting (W) and steel (Sl) loci of the mouse, respectively. Mutations at both the W and the Sl locus cause deficiencies in gametogenesis, melanogenesis and hematopoiesis (erythrocytes and mast cells). The W-sash mutation differs from most W mutations in that it affects primarily mast cells and melanogenesis but not other cellular targets of W and Sl mutations. Thus, Wsh/Wsh mice are fertile and not anemic, but they lack mast cells in their skin and intestine and are devoid of coat pigment. Heterozygotes are black with a broad white sash/belt in the lumbar region. In order to determine the basis for the phenotypes of W-sash mice, we investigated c-kit RNA and protein expression patterns in adult Wsh/Wsh mice and during embryonic development. We show that c-kit expression is absent in bone-marrow-derived Wsh/Wsh mast cells, the fetal and the adult lung, and the digestive tract at embryonic day 13 1/2 (E13 1/2), tissues that normally express c-kit. Unexpectedly, in E10 1/2 and 11 1/2d Wsh/Wsh embryos, we found c-kit expression in the dermatome of the somites, the mesenchyme around the otic vesicle and the floorplate of the neural tube, structures known to express the c-kit ligand in wild-type embryos. The ectopic c-kit expression in Wsh homozygous embryos does not affect c-kit ligand expression. The presumed Wsh/Wsh melanoblasts appeared to be normal and, at E10 1/2, similar numbers were found in normal and homozygous mutant embryos. At E13 1/2 +/+ embryos had a graded distribution of melanoblasts from cranial to caudal with a minimum in the lumbar region. Whereas E13 1/2 homozygous Wsh/Wsh embryos essentially lacked c-kit-positive cells in the skin, E13 1/2 heterozygous Wsh/+ embryos had reduced numbers of melanoblasts compared to +/+ with few or none in the lumbar region (future sash). It is proposed that ectopic c-kit expression in the somitic dermatome affects early melanogenesis in a dominant fashion. Molecular analysis of Wsh chromosomal DNA revealed a deletion or rearrangement in the vicinity of the c-kit gene. These results provide an explanation for the Wsh phenotype and have implications for the control of c-kit expression.
Duttlinger
R
R
Molecular Biology Program, Sloan Kettering Institute, New York, NY.
Manova
K
K
Chu
T Y
TY
Gyssler
C
C
Zelenetz
A D
AD
Bachvarova
R F
RF
Besmer
P
P
D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000032:analysis; D015971:Gene Expression Regulation, Enzymologic; D005865:Gestational Age; D008168:Lung / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism; D008543:Melanins / Q000096:biosynthesis*; D008544:Melanocytes / Q000378:metabolism; D008648:Mesoderm; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010859:Pigmentation Disorders / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D016184:Receptors, Colony-Stimulating Factor / Q000096:biosynthesis* / Q000235:genetics
D008543:Melanins; D011518:Proto-Oncogene Proteins; D016184:Receptors, Colony-Stimulating Factor; D004247:DNA; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases