Developmental mechanisms underlying polydactyly in the mouse mutant Doublefoot

Abstract

The pre-axial polydactylous mouse mutant Doublefoot has 6-9 digits per limb but lacks anteroposterior polarity (there is no biphalangeal digit 1). It differs from other polydactylous mutants in showing normal Shh expression, but polarizing activity (shown by mouse-chick grafting experiments) and hedgehog signalling activity (shown by expression of Ptc1) are present throughout the distal mesenchyme. The Dbf mutation has not yet been identified. Here we review current understanding of this mutant, and briefly report new results indicating (1) that limb bud expansion is concomitant with ectopic lhh expression and with extension of the posterior high cell proliferation rate into the anterior region, and (2) that the Dbf mutation is epistatic to Shh in the limb.

Fig. 1

Skeletal pattern in the right hindlimb of a wild type (a) and Doublefoot (b) pup at E17.5. This example of the Doublefoot phenotype shows an interdigital digit and a digital bifurcation; note absence of a biphalangeal digit 1.

Fig. 2

Hedgehog pathway gene expression patterns in wild type (left) and Dbf/+ (right) E10.5 embryos or limb buds; the Dbf/+ limb bud is expanded in most (d,f) but not all (b) embryos at this stage. (a,b) Ptc1 displays a posterior domain of expression in wild type limbs but is expressed throughout the distal limb bud mesenchyme in Dbf/+ (arrowed); (c,d) Shh expression is normal in the Dbf/+limb bud; (e,f) Ihh is not expressed in the E10.5 wild type limb bud, but in E10.5 Dbf/+ embryos it is expressed in the distal limb bud mesenchyme, excluding the Shh domain.