GENETIC CONTROL OF SKELETAL PATTERNING AND DEVELOPMENT

骨骼模式和发育的遗传控制

• 批准号: 6497446
• 负责人: THOMAS LUFKIN
• 金额: $ 33.24万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-16 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6497446
• 关键词: cell differentiation; developmental genetics; embryogenesis; gene expression; gene mutation; gene targeting; genetic screening; genetically modified animals; genome; histogenesis; homeobox genes; in situ hybridization; laboratory mouse; mesoderm; skeletal system; tissue /cell culture

The vertebrate skeleton is almost entirely mesodermal in origin, aside from several bones in the skull which are derived from neural crest (Noden, 1992; Couly et al., 1993). In Drosophila one of the principal genes controlling mesoderm differentiation is the bagpipe homeobox gene (Azpiazu and Frasch, 1993; Azpiazu et al., 1996). We have previously isolated from mouse and human, homologues of bagpipe termed Bapx1. Examination of the expression of Bapx1 during embryogenesis revealed an expression almost exclusively restricted to paraxial and lateral plate mesoderm, with earliest expression detectable in the presclerotome cells of the somite (Tribioli et al., 1997; Tribioli and Lufkin, 1997). During subsequent stages of embryogenesis, Bapx1 is expressed in essentially all cartilaginous condensations which will subsequently undergo endochondral ossification. To investigate the role of Bapx1 in embryonic skeletogenesis, this proposal focuses primarily on loss-of-function (gene knockout) and gain-of-function studies in vitro and in vivo. Preliminary results from mice lacking Bapx1 indicate that it plays an essential role in chondroblast differentiation within the axial skeleton, which in turn leads to failed endochondral ossification.

除了头盖骨中的几块骨头来自神经嵴外，脊椎动物骨骼几乎完全是中胚层的（Noden, 1992; Couly et al., 1993）。在果蝇中，控制中胚层分化的主要基因之一是风管同源盒基因（Azpiazu and Frasch, 1993; Azpiazu et al., 1996）。我们之前已经从小鼠和人类中分离出了风笛的同源物，称为Bapx1。对Bapx1在胚胎发生期间表达的检测显示，Bapx1的表达几乎完全局限于近轴和侧板中胚层，最早的表达可在体体细胞前细胞中检测到（Tribioli et al., 1997; Tribioli and Lufkin, 1997）。在胚胎发生的后续阶段，Bapx1基本上在所有软骨凝聚体中表达，这些软骨凝聚体随后会发生软骨内成骨。为了研究Bapx1在胚胎骨骼形成中的作用，本研究主要关注体外和体内功能缺失（基因敲除）和功能获得的研究。来自缺乏Bapx1的小鼠的初步结果表明，它在轴向骨架内的成软骨分化中起重要作用，从而导致软骨内成骨失败。