Project Details

Description

DESCRIPTION (provided by applicant): Cellular composition of the cerebral cortex is critical for normal function. While major deficits accompany extensive loss of tissue, more common problems like attentional/learning disability, schizophrenia and autism reflect more subtle changes undetected by neuroimaging. Specifically, abnormalities in numbers or types of neurons may underlie certain developmental disorders. As a corollary, deficiency in one neuron subpopulation due to disordered regulation at a specific ontogenetic stage may be compensated numerically by later neurogenesis, yielding an apparently normal cortical population size. Thus, by defining molecular regulation of neurogenesis, with regard to stage-specific cell production, we may discover pathways affecting cortical composition. We hypothesize signals stimulating precursor proliferation are balanced by anti-mitogenic regulators of extra- (PACAP) and intracellular (p57) origins, which halt cell cycle progression and impact cortical neurogenesis. We identified PACAP as one such anti-mitogenic agent, acting via G-protein coupled receptor/cAMP to inhibit cell cycle progression via increased CDK inhibitor, p57. We plan to define roles and mechanisms of anti-mitogenic signals in producing cortical populations. Our aims are: 1) Define the changes in cell cycle machinery elicited by intracerebroventricular injections of PACAP in utero, and identify responsive ventricular zone cells. 2) Characterize the roles of PACAP anti-mitogenic pathway components, specifically PAC1 receptor and CDK inhibitor p57, in promoting cell cycle exit and determining cell fate using deletion mutants. 3) Define effects of anti-mitogenic signaling on cell fate of mitotic precursors in culture and in vivo using over-expression vectors. Thus, we may gain insight into fundamental processes generating cellular diversity.
StatusFinished
Effective start/end date1/1/942/28/10

Funding

  • National Institute of Neurological Disorders and Stroke: $323,634.00
  • National Institute of Neurological Disorders and Stroke: $306,864.00
  • National Institute of Neurological Disorders and Stroke: $225,152.00
  • National Institute of Neurological Disorders and Stroke: $323,634.00
  • National Institute of Neurological Disorders and Stroke: $316,029.00
  • National Institute of Neurological Disorders and Stroke: $231,884.00
  • National Institute of Neurological Disorders and Stroke: $306,864.00
  • National Institute of Neurological Disorders and Stroke: $4,680.00

ASJC

  • Genetics
  • Molecular Biology
  • Cell Biology

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