The mouse mutants of the hemimelia-luxate group (lx, lu, lst, Dh, Xt, and the more
recently identified Hx, Xpl and Rim4; [1] [2] [3] [4] [5]) have in common preaxial
polydactyly and longbone abnormalities. Associated with the duplication of digits
are changes in the regulation of development of the anterior limb bud resulting in
ectopic expression of signalling components such as Sonic hedgehog (Shh) and fibroblast
growth factor-4 (Fgf4), but little is known about the molecular causes of this misregulation.
We generated, by a transgene insertion event, a new member of this group of mutants,
Sasquatch (Ssq), which disrupted aspects of both anteroposterior (AP) and dorsoventral
(DV) patterning. The mutant displayed preaxial polydactyly in the hindlimbs of heterozygous
embryos, and in both hindlimbs and forelimbs of homozygotes. The Shh, Fgf4, Fgf8,
Hoxd12 and Hoxd13 genes were all ectopically expressed in the anterior region of affected
limb buds. The insertion site was found to lie close to the Shh locus. Furthermore,
expression from the transgene reporter has come under the control of a regulatory
element that directs a pattern mirroring the endogenous expression pattern of Shh
in limbs. In abnormal limbs, both Shh and the reporter were ectopically induced in
the anterior region, whereas in normal limbs the reporter and Shh were restricted
to the zone of polarising activity (ZPA). These data strongly suggest that Ssq is
caused by direct interference with the cis regulation of the Shh gene.