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Blood, Vol. 94 No. 8 (October 15), 1999:
pp. 2658-2666
The Wsh, W57, and Ph
Kit Expression Mutations Define Tissue-Specific Control
Elements Located Between  23 and 154 kb Upstream of Kit
Georgina Berrozpe,
Inna Timokhina,
Steven Yukl,
Youichi Tajima,
Masao Ono,
Andrew D. Zelenetz, and
Peter Besmer
From the Molecular Biology Program Sloan-Kettering Institute, New
York, NY; and Cornell University Graduate School of Medical Sciences,
New York, NY.
The Kit and PDGFRa receptor tyrosine kinases are encoded in close
proximity at the murine white spotting (W) and patch
(Ph) loci. Whereas W mutations affect hematopoiesis,
melanogenesis, and gametogenesis, the Ph mutation affects
melanogenesis and causes early lethality in homozygotes. The
Wsh, W57, and Ph
mutations diminish Kit expression in certain cell types such as
mast cells and enhance it in others. The Wsh,
W57, and Ph mutations arose from deletions
and inversions affecting sequences in between the Kit and
PDGFRa genes. We have determined the precise location of the
breakpoint of the Wsh inversion and the endpoints
of the W57 deletion upstream of the Kit
transcription start site and examined the effect of these mutations on
Kit expression in mast cells and hematopoietic stem cells and lineage
progenitors. Our results indicate that positive elements controlling
Kit expression in mast cells mapping in between  23 and 154 kb
from the transcription start site can be dissociated from negative
elements controlling Kit misexpression during embryonic
development in the vicinity of the PDGFRa gene. In addition, we
have identified two clusters of hypersensitive sites in mast cells at
23 28 kb and 147 154 kb from the Kit gene
transcription start site. Analysis of these hypersensitive sites in
mutant mast cells indicates a role for HS4-6 in Kit expression
in mast cells. These findings provide a molecular basis for the
phenotype of these Kit expression mutations and they provide
insight into the complex mechanisms governing the regulation of
Kit expression.
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