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Mast cell number in the skin of heterozygotes reflects the molecular nature
of c-kit mutation
T Tsujimura, U Koshimizu, H Katoh, K Isozaki, Y Kanakura, T Tono, S Adachi, T Kasugai, H Tei and Y Nishimune
Department of Pathology, Medical School, Osaka University, Japan.
The W locus of mice encodes the c-kit receptor tyrosine kinase.
Heterozygous WJic/+ and Wn/+ mice and homozygous Wf/Wf mice were similar in
appearance; all of them have large depigmented areas lacking any
well-defined pattern. The WJic, Wn, and Wf mutant alleles were
characterized and their molecular nature was correlated with the mast cell
differentiation in the skin and the biologic features of cultured mast cell
(CMC). All WJic, Wn, and Wf were point mutations at the tyrosine kinase
domain, and c-kit mRNA was normally transcribed from all of them. The
mature 145-Kd form of the c-kit protein was produced from the WJic and Wf
alleles, but not from the Wn allele. c-kit proteins produced by the WJic or
Wf allele were expressed on the surface of CMCs, but those of the Wn allele
were not. When double heterozygous mice were produced between W and WJic
and between W and Wn, both W/WJic and W/Wn mice lacked skin mast cells.
W/WJic CMCs and W/Wn CMCs did not survive in the coculture with
fibroblasts. W/WJic CMCs normally attached to fibroblasts, but W/Wn CMCs
did not. The defect of W/Wn CMCs in the attachment was attributed to the
deficient extracellular expression of the c-kit protein. The number of skin
mast cells was compared among WJic/+, Wn/+, Wf/+, and Wf/Wf mice. Mast
cells decreased in WJic/+ and Wf/Wf mice, but not in Wn/+ and Wf/+ mice.
Although the Wn was a point mutation at the kinase domain, the biologic
effect of the Wn was comparable with that of the W mutant allele, which
produces truncated c-kit protein without the transmembrane domain. The weak
phenotype of Wn/+ mice may be explained by the deficient extracellular
expression of c-kit proteins produced by the Wn allele. When WJic/WJic,
Wn/Wn, and Wf/Wf CMCs were stimulated by the recombinant c-kit ligand,
autophosphorylation activity was observed only in Wf/Wf CMCs. This result
was consistent with the weak biologic effect of the Wf mutant allele.
Volume 81,
Issue 10,
pp. 2530-2538,
05/15/1993
Copyright © 1993 by The American Society of Hematology
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