GENETIC CONTROL OF SKELETAL PATTERNING AND DEVELOPMENT

脊椎动物骨骼几乎完全起源于中胚层，除了颅骨中的几个骨来源于神经嵴（Noden，1992; Couly等人，1993年）。 在果蝇中，控制中胚层分化的主要基因之一是风笛同源框基因（Azpiazu和Frasch，1993; Azpiazu等人，1996年）。 我们先前已经从小鼠和人类中分离出了风笛的同源物，称为Bapx 1。 在胚胎发生过程中对Bapx 1表达的检查揭示了几乎仅限于近轴和侧板中胚层的表达，在体节的前染色体节细胞中可检测到最早的表达（Tribioli等，1997; Tribioli和Lufkin，1997）。 在胚胎发生的后续阶段，Bapx 1基本上在所有软骨凝聚中表达，这些软骨凝聚随后将进行软骨内骨化。 为了研究Bapx 1在胚胎骨骼发生中的作用，该建议主要集中在体外和体内的功能丧失（基因敲除）和功能获得研究。 缺乏Bapx 1的小鼠的初步结果表明，它在中轴骨骼内的成软骨细胞分化中起着重要作用，这反过来又导致了软骨内骨化失败。

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.