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.
| Gu, Y; Sekiguchi, J; Gao, Y et al. (2000) Defective embryonic neurogenesis in Ku-deficient but not DNA-dependent protein kinase catalytic subunit-deficient mice. Proc Natl Acad Sci U S A 97:2668-73 |
| Pompeiano, M; Blaschke, A J; Flavell, R A et al. (2000) Decreased apoptosis in proliferative and postmitotic regions of the Caspase 3-deficient embryonic central nervous system. J Comp Neurol 423:12-Jan |
