One in two hundred children is born with limb deformities. An under- standing of the teleology of these defects, whether induced by taratogens, caused from a stochastic dysfunction of the developmental program, or the result of congenital defects, will require an under- standing of the normal process of limb development. Many of the genes that are suspected of mediating the formation of the limbs are now being identified. Particularly prominent among these genes is the set of Hox genes that may be required to specify the positional information needed for the establishment of the correct set of limb cartilages and bones. Gene targeting in mouse embryo-derived stem cells provides the means for generating mice with disruptions in each of these genes. The goal of this grant is to use gene targeting to undertake a systematic analysis of this gene complex and thereby directly establish the role of each of these genes in limb development. Not only will the phenotypic consequences of disrupting any particular gene be determined, but also through epistasis and molecular genetic analysis, it is hoped that insight will be gained as to how this set of genes functions as a network to determine the overall three-dimensional structure of the limb.
| Carroll, Lara S; Capecchi, Mario R (2015) Hoxc8 initiates an ectopic mammary program by regulating Fgf10 and Tbx3 expression and Wnt/?-catenin signaling. Development 142:4056-67 |
