GENETICS OF VERTEBRAL COLUMN DEVELOPMENT

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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.