Multigenic Control of the Localization of the Zone of Polarizing Activity in Limb Morphogenesis in the Mouse

AbstractWe report here that in three preaxial polydactylous mutants in the mouse, namely,lst, lx,andXpl,ectopic expression of theShhandFgf-4genes can be detected at the anterior margin of limb buds. These and three other mutants, namely,Rim4, Hx,andXtJ, which we described in our previous study, all appeared to form a duplicated zone of polarizing activity (ZPA) at the anterior margin of the limb bud. We studied the spatial and temporal pattern of expression of theGli3gene, which is affected in a loss-of-function type of mutation,XtJ. The expression domain ofGli3appeared to be complementary to the ZPA region and the gene was expressed prior toShh.The results support the hypothesis that GLI3 functions in the anterior portion of limb mesoderm to suppress the expression ofShh.InDrosophila,the geneci,the fly homologue ofGli,functions to represshh,suggesting that the negative regulation of the expression ofhedgehogby genes belonging to the GLI-kruppel family has been conserved from flies to mice. Finally, we found that the polydactylous phenotype of the mutantsRim4, Xt, lst,andlxcould be abrogated by the crossing with an inbred strain derived from wild mouse, MSM, whereas the phenotype ofXplcould not. These results indicate the presence of a modifier gene(s) that can influence the mutant phenotype and also that the mutations could be classified into two categories with regard to the mode of interaction with the modifier gene(s). Thus, this study revealed a multigenic control in the establishment of the anteroposterior axis in mouse limb development