The formation and patterning of the axial vertebral skeleton represent a time period of embryonic development highly susceptible to teratogenic agents, such as pesticides, pharmaceuticals, environmental toxicants, and physical entities, e.g. heat shock. The paraxial mesoderm derived somites are the embryonic precursors of the vertebrae. Mesodermal segmentation to form the somites and subsequent re-segmentation of the somites give rise to the repeated pattern of the vertebral column. Thus, defects of the vertebral column, such as fused, supernumerary and hemi-vertebrae, most likely result from perturbation of the process of somite segmentation and re-segmentation. Specific cell-cell and cell-matrix interactions are generally believed to regulate somite segmentation during embryogenesis; furthermore, these interactions are likely to be controlled, at least in part, by the expression of pattern-forming genes. Recent studies from a number of laboratories, including ours, have implicated members of the Pax gene family, homologs of the pair-rule gene family in Drosophila, as important in somite segmentation and re-segmentation. Our most recent findings indicate that several teratogenic agents, which perturb somite patterning and development, concomitantly affect the pattern and level of Pax- l gene expression in the somitic stage chick embryo. Experiments are proposed here to test the hypothesis that perturbations of somite segmentation, via alterations in the expression of specific genes such as the Pax genes, are involved in developmental teratogenesis of the spine and vertebral column. The information generated will be used to better define the site and mechanism of action of teratogenic agents which cause birth defects of the vertebral column. The chick embryo is proposed as the experimental model, in view of its easy accessibility to experimental manipulations and direct observations, and the existing wealth of information concerning cell/tissue fate and interactions during its development.
Two specific aims are proposed: I) to isolate and determine the structure of the avian Pax- l gene and to map its expression during normal somite development in order to gain insight into its potential biological function; and 2) to elucidate the relationship between altered Pax- I gene expression and somite teratotogenesis by a) demonstrating and characterizing the spatial and temporal disruptions in Pax- l gene expression accompanying toxic ant-induced somite teratogenesis, and b) analyzing the teratogenic effects on somite development as a result of experimentally perturbing Pax- l gene expression using both disruption and over-expression recombinant DNA approaches. These studies should shed light on the molecular mechanisms of teratogen-induced defects of the spine, as well as enhance our understanding of the basic biology of somite and vertebral development.
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