BMP in somite, cartilage and bone development

BMP 在体节、软骨和骨骼发育中的作用

• 批准号: 6336296
• 负责人: Richard R Behringer
• 金额: $ 18.82万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-15 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6336296
• 关键词: bone development; bone morphogenetic proteins; cartilage development; cell differentiation; chondrocytes; connective tissue development; developmental genetics; gene expression; gene targeting; genetic regulatory element; genetic transcription; genetically modified animals; growth factor receptors; laboratory mouse; mammalian embryology; normal ossification; protein structure function; recombinase

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.

该提案的主要目标是研究骨骼发育中骨形态发生蛋白（BMP）信号的需求。 BMP 是细胞因子转化生长因子-β 家族的成员，在脊椎动物发育过程中发挥多种不同的作用。 BMP 最初因其骨诱导能力而被发现，但它们还调节许多其他过程。 BMP Ia 型受体主要转导 BMP2 和 BMP4 信号。该受体在胚胎发生期间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。编码 IA 型 BMP 受体的 Bmp4 基因中存在靶向突变的纯合小鼠在发育早期死亡，未形成中胚层。此外，由 Bmpr 突变胚胎产生的畸胎瘤表明，Bmpr -/- 细胞具有分化成某些中胚层衍生组织（包括骨骼肌和软骨）的能力。 Bmpr 突变体的早期致死性使其无法用于研究胚胎发生后期或成体组织中 BMP IA 型受体的信号传导作用。我们通过小鼠胚胎干 (ES) 细胞中的基因靶向，在小鼠体内生成了 Bmpr 的条件 loxP 侧翼（floxed）等位基因。结合在特定组织中表达 cre 重组酶的转基因小鼠，我们建议检查 BMP 信号在体节、软骨和骨骼发育中的作用。这种条件遗传系统应该会带来关于骨骼系统发育中 BMP 信号的新见解。