Constitutively active canonical BMP signaling in the apical ectodermal ridge disrupts dorsal-ventral and anterior-posterior axes resulting in impaired development of the distal (autopod) limb domain

Throughout development the vertebrate limb requires the coordinated action of many signals to achieve its final complex 3 dimensional (3D) arrangement, and as such provides an excellent model in which to study pattern formation, morphogenesis, and homeostasis. The intricate mechanisms that govern these biological processes remain an active area of research. Bone Morphogenetic Proteins (BMPs) play an integral role in the morphogenesis of the developing limb, however the precise details of this role continues to be unraveled. To further study the role of BMP signaling in the developing limb we have generated transgenic mice harboring a constitutively active form of the BMPR1A receptor under an Msx2 promoter. In early mouse development this short form of the Msx2 promoter drives expression of the transgene specifically in the ventral ectoderm, particularly in the apical ectodermal ridge (AER) which is one of the major signaling centers of the developing limb bud. With transgene expression limb development is markedly impaired. Entire distal limb segments are truncated in both forelimbs and hind limbs, whereas portions of the proximal and the middle segments of hind limbs are also shortened and slightly deformed. Expression of key patterning genes is altered in both the mesoderm and surrounding ectoderm, and dorsal-ventral (D-V) and proximal-distal (P-D) axes formation is perturbed. This disruption in limb development implicates BMP as not only a crucial player in morphogenesis, but exposes the dynamic role it plays in 3 dimensional (3D) limb patterning through an intricate network of signaling pathways and feedback loops.