The origins of neural tube defects (NTDs) and, indeed, of factors responsible for neurulation itself are poorly understood. One reason for this lack of understanding is the complexity of the process, which involves coordination among multiple cell types and intra- and extracellular events to successfully complete neurulation. Disruption of any of these events can result in an abnormality. one such event is cell death, which occurs normally (physiological) during neurulation and contributes to the process, but which may be increased by teratogens and/or genetic causes and contribute to NTDs. This project will examine the role of cell death in normal and abnormal development using the curly tail (ct) mouse mutant and gene-teratogen interactions as models. Also, potential regulation of cell death by retinoic acid, its receptors and its binding proteins will be investigated. These goals will be accomplished by: 1) determining the patterns of cell death in specific cell populations in ct and control mice and comparing these patterns to those produced by teratogens known to affect specific cell populations, i.e. valproate and alcohol (neuroepithelial and primitive streak cells) and retinoic acid (gut endoderm and primitive streak cells) ; 2) determining the sensitivity of ct embryos to teratogen exposure, i.e. gene teratogen interactions; 3) determining the roles of zinc, folate, and superoxide dismutase as potential factors for preventing or curing NTDs; 4) determining the patterns of expression of retinoic acid receptors and binding proteins (CRBP and CRABP) in the presence and absence of retinoids using in situ hybridization and a transgene with a LacZ reporter; 5) determining the function of the retinoic acid receptors and binding proteins using antisense oligonucleotides and whole embryo culture. Together these studies will provide information on the pathogenesis and mechanisms of NTDs in ct and normal mice and will enhance the understanding of this morphogenetic event. In turn, the results may suggest avenues of prevention for birth defects such as spina bifida.
