COOPERATION BETWEEN NF1 AND P53 IN NEURAL DEVELOPMENT

Project: Research project

Project Details

Description

DESCRIPTION: 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.
StatusFinished
Effective start/end date9/30/988/31/00

Funding

  • National Institutes of Health

ASJC

  • Medicine(all)

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