Multiple roles of BMP signaling in mouse development

Abstract

The bone morphogenetic proteins (BMPs) are a large family of secreted ligands within the TGF-beta superfamily that play essential roles in embryonic development. BMP functions are antagonized by a large number of secreted proteins such as Noggin, Chordin, Follistatin and the DAN family members (Gremlin, Cerberus, DAN and others) that bind BMPs extracellularly, thereby preventing binding of the BMPs to their receptors. Members of the dpp (drosophila decapentaplegic) family of the BMPs, BMP2 and 4 and the 60A subfamily member, BMP7 (also known as OP1), as well as their inhibitor Noggin, have very specific temporal and spatial expression pattern in the developing sensory ganglia, the targets of the sensory neurons including the skin, the hair follicles and the developing limb bud. The specific roles played by the BMPs in these systems during their morphogenesis later in development has been difficult to elucidate due to the complex expression pattern of the above BMP ligands and their inhibitors, compounded by the fact that experimentally generated mouse mutants of the BMP ligands such as BMP2, 4 as well as their receptors are lethal early in development. In order to study BMP signaling in mouse development in vivo, we inhibited the signaling pathway by overexpressing the BMP inhibitor, Noggin in the skin by the keratin-14 (K14) promoter and neurons by the Neuron-specific enolase (NSE) promoter. These mice were viable with specific phenotypes. Studies in the K14-Noggin mice showed that BMP signaling regulates the extent of peripheral skin innervation as well as neuron number in sensory ganglia. Analysis of the limb phenotype of the same transgenic mice showed that BMP signaling is essential for apoptosis in the developing limb bud. Misexpression of the BMP inhibitor Noggin in neurons, merkel cells and melanocytes of the hair follicles of NSE-noggin mice resulted in a block in differentiation of the nontylotrich hair follicles and premature onset of catagen of those follicles resulting in a loss of more than 80% of hair in the adult mouse. In summary, the above mouse models showed that BMP signaling regulates proliferation, differentiation and survival of specific tissues depending upon the context of temporal and spatial environment.