BMP in somite, cartilage and bone development

本研究的主要目的是探讨骨形态发生蛋白（BMP）信号在骨骼发育中的作用。BMP是细胞因子的转化生长因子-β家族的成员，其在脊椎动物发育期间发挥各种不同的作用。骨形成蛋白最初被鉴定为它们的骨诱导能力，但它们也调节许多其他过程。BMP Ia型受体主要转导BMP 2和BMP 4信号。该受体在胚胎发生和成体组织中广泛表达，表明该受体可以在许多组织中介导BMP信号。对于编码BMP IA型受体的Bmp 4基因中的靶向突变纯合的小鼠在发育早期死亡，而不形成中胚层。此外，从Bmpr突变胚胎产生的畸胎瘤表明，Bmpr -/-细胞包括其分化成某些中胚层来源的组织，包括骨骼肌和软骨的能力。Bmpr突变体的早期致死性排除了它们在研究通过BMP IA型受体在胚胎发生后期或成体组织中的信号传导作用中的有用性。我们已经产生了一个条件loxP侧翼（floxed）等位基因的Bmpr在小鼠中的基因靶向小鼠胚胎干细胞（ES）。结合在特定组织中表达cre重组酶的转基因小鼠，我们建议研究BMP信号在体节、软骨和骨发育中的作用。这种有条件的遗传系统应导致新的见解BMP信号在骨骼系统的发展。

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.