Neurogenesis and pathogenesis of the dysraphic neural tube.

Defects in neurulation occur in roughly 4,000 pregnancies in the United States, and approximately 400,000 pregnancies worldwide each year. Infants born with caudal neural tube defects (NTDs) are usually paralyzed, with bowel and bladder incontinence. Numerous genetic loci and environmental agents interact to produce NTDs, making prevention of these defects difficult. Therefore, it is essential to begin to understand the postneurulation pathology that results in clinical disabilities. The purpose of this dissertation is to begin to explore this pathology. The chapters herein examine the differentiation, organization, and proliferation of cells in the dysraphic neural tube of two mouse neural tube mutants, curly tail and splotch-delayed. The results of these studies suggest that closure of the neural tube is not essential for normal neuronal or glial differentiation between embryonic days 12 and 15 (E12-E15). However, maturation of the spinal cord is halted after E16, when a massive deterioration of the neural tissue begins. Additionally, our results suggest that the temporal pattern of cell proliferation is similar between normal and affected embryos. By contrast, the number of postmitotic cells in affected embryos is significantly increased during several days of gestation. Measurements of the volume of neuronal tissue suggested that more neurons were born in affected embryos than the control. Thus, failure of the neural folds to close may adversely affect the quantity of proliferation. In addition to the experiments described above, we also examined the percentage of embryos born with spina bifida in the curly tail strain. The results suggest that the incidence of NTDs in this mutant is much lower than reported in the literature. The final study examined the location of mitotic figures in spina bifida embryos to determine whether cells undergo mitosis within the ventricular zone. The outcome of this study revealed that the nuclei of dividing cells are able to translocate to the ventricular zone.