Absence of radius and ulna in mice lacking hoxa-11 andhoxd-11

Abstract

Mice with targeted disruptions in Hox genes have been generated to evaluate the role of the Hox complex in determining the mammalian body plan. This complex of 38 genes encodes transcription factors that specify regional information along the embryonic axes. Early in vertebrate evolution an ancestral complex shared with invertebrates was duplicated twice to give rise to the four linkage groups (Hox A, B, C and D). As a consequence, corresponding genes on the separate linkage groups, called paralogues, are most closely related to each other. Based on sequence similarities, the Hox genes have been subdivided into 13 paralogous groups. The five most 5' groups (Hox 9-13) pattern the posterior region of the vertebrate embryo and the appendicular skeleton. Mice with individual mutations in the paralogous genes hoxa-11 and hoxd-11 have been described. By breeding these two strains together we have generated double mutants which have dramatic phenotypes not apparent in mice homozygous for the individual mutations. The radius and the ulna of the forelimb are almost entirely eliminated, the axial skeleton shows homeotic transformations, and there are severe kidney defects not present in either single mutant. The limb and axial phenotypes are quantitative: as more mutant alleles are added to the genotype, the phenotype becomes progressively more severe. The appendicular skeleton defects suggest that paralogous Hox genes function together to specify limb outgrowth and patterning along the proximodistal axis.

Comparative spatiotemporal analysis of Hox gene expression in early stages of intermediate mesoderm formation

“…Recent loss-of-function studies in mice demonstrated a pivotal role for Hox10 and Hox11 in metanephric kidney development (Gong et al, 2007;Yallowitz et al, 2009Yallowitz et al, , 2011. Loss of paralogous group 11 genes causes mesenchymal defects exhibited in aberrant branching morphogenesis or agenesis (Davis et al, 1995;Patterson et al, 2001;Wellik et al, 2002) and results in altered expression of many kidneys markers, including Gdnf, Six-2, Bf-2, Pax-2, and Integrin a8 (Patterson et al, 2001;Valerius et al, 2002;Wellik et al, 2002;Mugford et al, 2008). Loss of paralogous Hox10 genes causes the loss of cortical stromal cell function results in undifferentiated kidney capsule along with aberrant ureter branching (Yallowitz et al, 2011).…”

A mutational analysis of the 5′ Hoxd genes: dissection of genetic interactions during limb development in the mouse

“…In support of this idea, it has been demonstrated that Hox paralogues function together to specify both the axial and appendicular skeleton of the mouse (Condie and Capecchi, 1994;Davis et al, 1995;Horan et al, 1995). Additionally, it has been shown (hoxd-11/hoxd-12) and (hoxd-12/hoxd-13) transheterozygotes.…”

“…These genes are activated in a strictly regulated temporal and spatial pattern during development such that the more 3′ gene (hoxd-12) is expressed earlier and in a more proximal domain than the more 5′ gene (hoxd-13; Duboule, 1992;Izpisúa-Belmonte and Duboule, 1992). This feature of temporal and spatial colinearity of Hox genes may play an important role in limb patterning by determining regional identity along the appendicular axis and controlling the properly timed cellular proliferations required for the building of the limb (Davis et al, 1995;Duboule, 1995). To analyze the role of these genes in limb development, we have created targeted disruptions in mice (Capecchi, 1989).…”

“…The 5′ ends of the Hox loci carry the five paralogous gene families Hox9-13. Mutational analysis of some of these genes has demonstrated that they play an important role in limb development (Dollé et al, 1993;Small and Potter, 1993;Davis and Capecchi, 1994;Davis et al, 1995;Favier et al, 1995).…”

Molecular basis for skeletal variation: insights from developmental genetic studies in mice

“…Indeed, elements of the skeleton develop abnormally when Hox genes are misexpressed in transgenic mice (Charite et al, 1994;Jegalian and DeRobertis, 1992;Kessel et al, 1990;Lufkin et al, 1992;Pollock et al, 1992). Similarly, the disruption of Hox genes by targeted mutagenesis leads to alterations in the skeleton (Boulet and Capecchi, 1996;Boulet and Capecchi, 2002;Capecchi, 1993, 1994;Capecchi, 1994, 1996;Davis et al, 1995;Favier et al, 1995;Favier et al, 1996;Fromental-Ramain et al, 1996a;Fromental-Ramain et al, 1996b;Horan et al, 1995a;Horan et al, 1994;Kostic and Capecchi, 1994;LeMouellic et al, 1989;RamirezSolis et al, 1993;Rancourt et al, 1995;Rijli et al, 1994;Rijli et al, 1993;Rijli et al, 1995;Saegusa et al, 1996;Small and Potter, 1995;Suemori et al, 1995. Analogous to mutant phenotypes in the fruitfly Drosophila, the pattern abnormalities in vertebral shape and identity have generally been interpreted as homeotic transformations.…”