GENETICS OF VERTEBRAL COLUMN DEVELOPMENT

脊柱为身体提供机械支撑，并封闭 并保护脊髓。它由体节发展而来，一系列 在早期胚胎中排列的同源细胞块 神经管的任一侧沿前后轴线。 脊索发出的信号对躯体来说起着至关重要的作用 模式和分化因此，脊索缺陷 功能、发育或完整性导致畸形或发育不全 脊椎的，通常与神经学有关， 泌尿生殖或肛门直肠缺陷。 了解正常和异常背后的分子机制 脊柱发育、隔离和功能 相关基因的特性是至关重要的。分析了几个问题 突变体是分离这类基因的关键。在本提案中，我们将 重点分析截短(TC)突变，这会导致 特发于下腰椎的脊柱畸形和发育不全 和骶骨区域。这些缺陷是由有缺陷的脊索引起的 仅在其尾部区域发展。截断操作非单元格 自发地，暗示TC影响一个基本信号(S) 特别是后部脊索发育所必需的 身体轴线的位置。 这项提议的目标是确定无弦乐队是否 规格或形态发生是否受到影响，以及表达是否 已知的信号分子的性质或数量发生了改变 在TC突变胚胎中，对TC基因进行鉴定。这将是 通过研究突变表型的个体发育来完成 截尾的分子标记、精细遗传和物理作图 突变，并测试从关键基因分离的候选基因 通过转基因方法检测含TC的间隔。 对截短突变和受影响基因的分析应该会有所帮助 要了解控制Notochord的信号机制 发展，并最终阐明这些问题的意义 人类尾部退行性综合征的个体发育机制。

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.