Msx1 and Msx2 in limb mesenchyme modulate digit number and identity

Abstract

Msx1 and Msx2 encode homeodomain transcription factors that play a crucial role in limb development. However, the limb phenotype of the double Msx1 null/null Msx2 null/null mutant is difficult to analyze, particularly along the anteroposterior axis, because of the complex effects of the double mutation on both ectoderm-and mesoderm-derived structures. Namely, in the mutant, formation of the apical ectodermal ridge (AER) is impaired anteriorly and, consequently, the subjacent mesenchyme does not form. Using the Cre/loxP system, we investigated the respective roles of Msx genes in ectoderm and mesoderm by generating conditional mutant embryos with no Msx activity solely in the mesoderm. In these mutants, the integrity of the ectodermderived AER was maintained, allowing formation of the anterior mesenchyme. With this strategy, we demonstrate that mesenchymal expression of Msx1 and Msx2 is required for proper Shh and Bmp4 signaling to specify digit number and identity.

LIM homeobox transcription factor Lhx2 inhibits skeletal muscle differentiation in part via transcriptional activation of Msx1 and Msx2

“…This is consistent with previous reports showing overlapping expression of Lhx2 and Msx1 genes at the leading edge of mouse limb buds, and coexpression of their fly orthologues in Drosophila wing discs [12]. Our finding is also consistent with the observation that limb development is severely impaired in Msx1/Msx2 double knockout mice [22,25] and Lhx2/Lhx9 double knockout mice [13]. Among 11 LIM homeobox transcription factors, Lhx9 is phylogenetically closest to Lhx2 [26]; thus it is likely that Lhx9 activity is complementary to Lhx2-mediated induction of Msx1/Msx2 expression.…”

Microduplications upstream ofMSX2are associated with a phenocopy of cleidocranial dysplasia

“…The complex synpolydactyly of the hands in P2 is reminiscent of hand malformations caused by spatiotemporal disruption of Hedgehog signalling. Recently, it has been shown that Msx1 and Msx2 expression in the limb mesenchyme modulates digit number and identity via the Shh and Bmp signalling pathways 28. The forelimb phenotype in these mice shows striking similarities to the complex synpolydactyly of the hands which we observed in P2.…”

A Novel Heterozygous Intragenic Sequence Variant in DLX6 Probably Underlies First Case of Autosomal Dominant Split-Hand/Foot Malformation Type 1

“…Double knock out of Dlx5/6 in mice resulted in phenotypes similar to human SHFM1 [Merlo et al, 2002;Robledo et al, 2002]. Double inactivation of Msx1 and Msx2 in mice caused polydactyly in the forelimbs and oligodactyly in the hindlimbs [Lallemand et al, 2005;Bensoussan-Trigano et al, 2011]. Triple knockout mice involving Msx1 , Dlx5 , and Dlx6 developed phenotypes similar to those of Msx1 and Msx2 double knockout mice, while phenotypes of Msx2 , Dlx5 , and Dlx6 triple knockout mice were similar to Dlx5/6 double knockout mice.…”