The primary goal of this proposal is to investigate the requirement of bone morphogenetic protein (BMP) signals in skeletal development. BMPs are members of the transforming growth factor-beta family of cytokines that play a variety of different roles during vertebrate development. BMPs were first identified for their bone-inducing abilities but they also regulate many other processes. The BMP type Ia receptor primary transduces BMP2 and BMP4 signals. This receptor is widely expressed during embryogenesis and in adult tissues, suggesting that this receptor can mediate BMP signals in many tissues. Mice that are homozygous for a targeted mutation in the Bmp4 gene that encodes the BMP type IA receptor die early in development without forming mesoderm. In addition, teratomas generated from Bmpr mutant embryos suggested that Bmpr -/- cells are comprised their abilities to differentiate into certain mesodermally-derived tissues, including skeletal muscle and cartilage. The early lethality of the Bmpr mutants precludes their usefulness in investigating the role of signaling through the BMP type IA receptor at later stages of embryogenesis or in adult tissues. We have generated a conditional loxP-flanked (floxed) allele of Bmpr in mice by gene targeting in mouse embryonic stem (ES) cells. In combination with transgenic mice that express cre recombinase in specific tissues, we propose to examine the role of BMP signals in somite, cartilage and bone development. This conditional genetic system should lead to new insights regarding BMP signals in the development of the skeletal system.
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