Neural tube defects are among the most common birth defects in humans, and can lead to paralysis, hydrocephaly, and death. The development of a normal CNS requires a delicate balance of cell proliferation and programmed cell death that ultimately determine the number and type of progenitors and their differentiated progeny. This complex developmental program involves signaling cascades that mediate proliferation, differentiation, and apoptosis. Two molecules: neurofibromin, known to be a negative regulator of p21ras signaling protein encoded by the neurofibro-matosis type I (Nf1) gene, and p53, a transcriptional regulator of cell cycle progression and apoptosis are involved in normal CNS development. In mice with targeted inactivating mutations, loss of either neurofibromin or p53 leads to enhanced survival and proliferation of embryonic mouse peripheral neurons while inactivation of both genes in the double knock-out causes increased incidence of exencephaly, in which the cranial neural tube fails to close. The applicant proposes to extend these observations and determine whether this extreme CNS phenotype stems from inappropriate number of cells (or timing or shape) as a result of combination of increased cell proliferation due to the absence of neurofibromin, which can act to inhibit signaling through p21ras and its downstream effectors, and reduced levels of apoptotic cell death stemming from the absence of p53 which can promote cell cycle arrest and apoptosis through transcriptional regulation.
Aim 1 will determine whether the high incidence of cranial neural tube closure defects in the double knock-out mice results from aberrations in neuroepithelial cell cycle regulation, programmed cell death, and response to environmental clues.
Aim 2 will test whether neurofibromin and p53 regulate the behavior of different subsets of neural crest derived cells and mediate different signal transduction events in these cells. Finally the applicant will determine whether neurofibromin acts in processes that affect cell survival, as well as axon growth rate and innervation pattern.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
James A. Shannon Director's Award (R55)
Project #
1R55HD036222-01
Application #
2878053
Study Section
Neurology C Study Section (NEUC)
Project Start
1998-09-30
Project End
2000-08-31
Budget Start
1998-09-30
Budget End
2000-08-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Louisiana State University Hsc New Orleans
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112