GENETICS OF VERTEBRAL COLUMN DEVELOPMENT

脊柱为身体提供机械支撑， 保护脊髓 它从体节发展而来， 在早期胚胎中排列的同源细胞块， 沿着前后轴的神经管沿着。 从脊索发出的信号对体节起着重要作用 因此，脊索的缺陷 功能、发育或完整性导致畸形或发育不全 脊柱的损伤，通常与神经系统有关， 泌尿生殖系统或肛门直肠缺陷。 了解正常和异常的分子机制 脊柱发育，分离和功能 对相关基因的鉴定至关重要。分析 突变体是分离这些基因的关键。 在本提案中，我们将 重点分析截短（tc）突变，这导致 椎体畸形和发育不全，特别是在下腰椎 和骶骨区。 这些缺陷是由有缺陷的脊索引起的 仅在其尾部区域发育。 截断非细胞行为 自主地，表明TC影响一个重要信号 后区脊索发育特别需要的 身体轴的。 这项提案的目的是确定， 规格或形态发生受到影响，以及表达是否 已知的信号分子被定性或定量地改变 在TC突变胚胎中，并鉴定TC基因。 这将是 通过研究突变体表型的个体发生来完成， 分子标记、精细遗传和物理作图 突变，并测试候选基因分离的关键 通过转基因方法获得含有TC的间隔。 对截短突变和受影响基因的分析应该有助于 了解控制脊索的信号机制 发展，并最终阐明这些意义 人类尾部退化综合征的个体发生机制。

The vertebral column lends mechanical support to the body, and encloses and protects the spinal cord. It develops from the somites, a series of homologous blocks of cells that are arranged in the early embryo on either side of the neural tube along the anterior-posterior axis. Signals emanating from the notochord play essential roles for somite patterning and differentiation consequently, defects in notochord function, development, or integrity lead to malformations or agenesis of the vertebral column, frequently associated with neurological, urogenital or anorectal defects. To understand the molecular mechanisms underlying normal and abnormal vertebral column development, the isolation and functional characterization of the relevant genes is essential. The analysis of mutants is the key to isolate such genes. In this proposal we will focus on the analysis of the truncate (tc) mutation, which leads to vertebral malformations and agenesis specifically in the lower lumbar and sacral region. These defects are caused by defective notochord development only in its caudal region. Truncate acts non-cell autonomously, suggesting that tc affects an essential signal(s) specifically required for notochord development in the posterior region of the body axis. The goals of this proposal are to determine, whether notochord specification or morphogenesis is affected, and whether the expression of known signaling molecules is qualitatively or quantitatively altered in tc mutant embryos, and to identify the tc gene. This will be accomplished by studying the ontogeny of mutant phenotype using molecular markers, fine genetic and physical mapping of the truncate mutation, and testing candidate genes isolated from the critical interval containing tc by transgenic approaches. The analysis of the truncate mutation and the affected gene should help to understand the signaling mechanisms controlling notochord development, and ultimately elucidate the significance of these mechanisms for the ontogeny of caudal regression syndromes in humans.