Paired-Related Homeobox Genes Cooperate in Handplate and Hindlimb Zeugopod Morphogenesis

AbstractThe closely related homeobox genesprx-1andprx-2are expressed in lateral plate and limb bud mesoderm, but targeted inactivation of these genes failed to demonstrate a limb phenotype. Here we report that mice carrying compound mutations inprx-1andprx-2have severe limb deformities. In the forelimb autopod, pre- and postaxial polydactyly were found most commonly, but also syndactyly, oligodactyly, and abnormal digit placement affecting posterior elements were observed. In the hindlimb, preaxial polydactyly with variable expressivity was seen in all cases. Extreme distal digit duplications were seen in both the fore- and hindlimbs.prx-1; prx-2double-mutant mice also displayed extreme shortening and impaired ossification of the hindlimb zeugopods. Integrity of the forelimb apical ectodermal ridge was abnormal as determined by expression ofFGF8andBMP4.Expression ofmsx-1andmsx-2,markers forBMPsignaling pathways, was absent in regions of the posterior handplates, while expression ofShhandpatchedwas unaffected. The mutant phenotypes were dosage dependent, sinceprx-1 −/−; prx-2 +/−mice also displayed severe limb abnormalities. These data suggest thatprx-1andprx-2cooperatively regulate handplate and hindlimb zeugopod morphogenesis throughBMP-mediated signaling pathways