GENETIC CONTROL OF SKELETAL PATTERNING AND DEVELOPMENT

骨骼模式和发育的遗传控制

• 批准号: 6628128
• 负责人: THOMAS LUFKIN
• 金额: $ 34.24万
• 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/6628128
• 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.

脊椎动物的骨骼几乎完全是中胚层的起源，除了颅骨中的几个骨头源自神经rest（Noden，1992; Couly等，1993）。 在果蝇中，控制中胚层分化的主要基因之一是风笛同源基因（Azpiazu和Frasch，1993; Azpiazu等，1996）。 以前，我们已经从小鼠和人类中分离出来，风笛的同源物称为BAPX1。 对胚胎发生过程中BAPX1表达的检查表明，表达几乎仅限于近端和侧板中胚层，最早的表达在somite的预蛋白酶细胞中可检测到（Tribioli et al。，1997; Tribioli and Lufkin，1997）。 在随后的胚胎发生阶段，BAPX1在所有软骨凝结中表达，随后将经历内软骨的骨化。 为了研究BAPX1在胚胎骨骼生成中的作用，该建议主要集中于功能丧失（基因敲除）和功能性研究的体外和体内。 缺乏BAPX1的小鼠的初步结果表明，它在轴向骨骼内的软骨细胞分化中起着至关重要的作用，进而导致内软骨内侧骨化失败。