Neurological disorders that stem from cortical neuron dysfunction result in part from the disruption of normal developmental processes within the cerebral cortex. The long-term goal of this proposal is to understand how cortical neurons are produced and selected to achieve the populations that are found normally in the healthy adult brain. The production and initial selection of cortical neurons occur during prenatal life. Many previous studies have identified major features of embryonic development in the central nervous system (CNS) that include neuronal generation within proliferative zones adjacent to the ventricles (the ventricular zone), migration to more superficial locations and subsequent differentiation, and lineage or cohort relationships as revealed by the use of retroviruses. All of these studies have assumed, either explicitly or implicitly, that a negligible amount of programmed cell death (PCD or """"""""apoptosis"""""""") occurs during this embryonic phase of cortical development. If, however, PCD is pervasive, then it could have an important role in determining the cells that are present during postnatal life. I will thus test the hypothesis that apoptosis differentially affects ventricular zone neuroblast subpopulations and early postmitotic cortical neurons. I will test the hypothesis in 3 specific Aims over the next 5 years.
Aim 1 will identify global anatomical and developmental gradients of apoptotic cells during embryonic cortical development (e.g. dorsal-ventral, lateral-medial, rostral-caudal), relate the gradients to proliferative and postmitotic compartments, and determine how these gradients are affected in Balb/c and cell death mutant mouse CPP32 +/+ (wild-type) as compared to +/-(heterozygote) and -/(homozygote) embryos (Years 1-3).
Aim 2 will determine the effect of apoptosis on ventricular zone neuroblast subpopulations in Balb/c and CPP32 +/+ (wild-type) as compared to +/-(heterozygote) and -/- (homozygote) embryos; these studies will focus on identified cells within the ventricular zone (as defined by vzg-1 in situ hybridization). Years 1-5.
Aim 3 will determine the effect of apoptosis on embryonic, postmitotic neurons within postmitotic neuroanatomical compartments (defined by png-I in situ hybridization) in Balb/c and CPP32 +/+, +/- and -/- embryos. (Years 1-5). This information will provide new insights into the mechanisms behind developmental neurological disorders, especially those affecting the normal functions of the cerebral cortex.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036949-03
Application #
6187776
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Spinella, Giovanna M
Project Start
1998-07-08
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
3
Fiscal Year
2000
Total Cost
$190,802
Indirect Cost
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093