The long-term objectives of this research are to understand the normal process of neurulation, which results in the formation of a closed neural tube, the precursor of the entire central nervous system, and to understand the mechanisms by which this critical process is disrupted in the genesis of neural tube defects (NTDs). NTDs, such as spina bifida, are among the most common and most severe human congenital malformations. Neurulation in mice is for all practical purposes identical to that in humans. In addition, a number of genetically mutant mice are available as animal models of the human disease, and these offer the distinct advantage that they provide a continuous and reproducible source of experimental material. A thorough understanding of such animal models could eventually lead to the prevention or treatment of human NTDs. One of the first aims of this research is to define the patterns of cell movements and changes in cell shapes that occur during normal neurulation in mammals. In addition, normal cell fates and lineages in the epiblast and mesoblast will be determined. Having characterized these processes in normal mice, they will be examined in the curly tail mutant mouse to determine if any are disrupted and causally related to the neural tube defect. These events will be studied in whole embryo cultures using a variety of enzyme, fluorescent, and retroviral markers to follow the movements of cells. It is obvious that if you prevent the neural tube defect, you will prevent the resulting neurological impairments. However, in lieu of total prevention of the defect, it is of extreme clinical importance to reduce the neurological deficits. The curly tail mutant provides a unique opportunity to examine the effects of NTDs on neuronal differentiation to determine if there are critical periods during which the open neural tube is most damaging to the nervous system. This will be examined using several monoclonal antibodies to monitor neuronal differentiation in curly tail mice and to compare the results to normal littermates. Finally, a variety of genetic studies will be conducted to determine the chromosomal location of the curly tail gene and to identify closely linked genetic markers. In addition, attempts will be made to find a genetic background that will improve the penetrance and expressivity of this mutant and to identify other genetic loci that modify the expression of the disease. These other genes could offer important clues to the causes of NTDs and possible means of prevention.
Showing the most recent 10 out of 25 publications
