BMP in somite, cartilage and bone development

这项建议的主要目的是研究骨形态发生蛋白(BMP)信号在骨骼发育中的需求。BMP是细胞因子转化生长因子-β家族的成员，在脊椎动物的发育过程中扮演着各种不同的角色。BMP最初被发现是因为它们的成骨能力，但它们也调节着许多其他的过程。BMP Ia型受体主要转导BMP2和BMP4信号。该受体在胚胎发育和成体组织中广泛表达，提示该受体可在许多组织中介导BMP信号。编码BMP IA受体的Bmp4基因的目标突变纯合的小鼠在发育早期就会死亡，没有形成中胚层。此外，从Bmpr突变胚胎产生的畸胎瘤表明，Bmpr-/-细胞具有分化为某些中胚层组织的能力，包括骨骼肌和软骨。Bmpr突变体的早期致死性排除了它们在研究BMP I型受体在胚胎发育后期或成人组织中的信号作用方面的作用。我们通过在小鼠胚胎干细胞(ES)中进行基因打靶，在小鼠体内产生了Bmpr的条件性loxP侧翼(开花)等位基因。结合在特定组织中表达cre重组酶的转基因小鼠，我们建议检测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该会对骨骼系统发育中的BMP信号产生新的见解。

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.