The regulation of cell number and, more specifically, neuron number in the developing CNS is a largely unexplored question. Any answer to this question must consider two important developmental issues: 1) the regulation of neuronal production and 2) the phenomenon of naturally occurring cell death. This project is concerned with the first of these issues. We will determine: 1) how the relative number of proliferative cells changes during the development of a structure, 2) how frequently the proliferative cells divide, and 3) what proportion of the proliferative population becomes permanently post-mitotic at each pass through the cell cycle. We will examine this issue in four different proliferative zones in the developing hippocampal region of the mouse: 1) the ventricular zone of the hippocampus and subiculum, 2) the ventricular zone of the periallocortex (presubiculum, parasubiculum and entorhinal area, 3) the subventricular zone of the periallocortex, and 4) the intrahilar proliferative zone of the dentate gyrus. We will measure the length of the cell cycle (Tc) and the DNA-synthetic phase (Ts) for all of the proliferative population and also for that subpopulation which will produce neurons. For several ages, the proportion of the daughter cells that leave the proliferative zones to become permanently post-mitotic will be determined to test the hypothesis that during developing that proportion increases gradually such that the proliferative population becomes self-exhausting several generations before cell proliferation for that structure ceases. The output of the proliferative zones will be measured by determining the distribution of cells that leave each of the four proliferative populations within a one-hour period (i.e., a """"""""one-hour cohort""""""""). The pattern of distribution of labeled cells from retroviral infections for progeny from three of the four different proliferative populations will be determined. We will develop three probabilistically- driven cytogenetic and histogenic models, a cytokinetic model, and output (or cell proliferation) model, and a cell dispersion model. The model will be used to determine if the results of the various experiments are consistent internally and with each other and to make specific testable predictions. The major methods to be used are: 1) bromodeoxyuridine immunohistochemistry and tritiated thymidine autoradiography both alone and in a series of double labeling experiments, and 2) retroviral transfection of clonally related populations.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurology B Subcommittee 2 (NEUB)
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University of Medicine & Dentistry of NJ
Schools of Medicine
United States
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Takahashi, T; Nowakowski, R S; Caviness Jr, V S (1997) The mathematics of neocortical neuronogenesis. Dev Neurosci 19:17-22
Cai, L; Hayes, N L; Nowakowski, R S (1997) Synchrony of clonal cell proliferation and contiguity of clonally related cells: production of mosaicism in the ventricular zone of developing mouse neocortex. J Neurosci 17:2088-100
Cai, L; Hayes, N L; Nowakowski, R S (1997) Local homogeneity of cell cycle length in developing mouse cortex. J Neurosci 17:2079-87
Takahashi, T; Nowakowski, R S; Caviness Jr, V S (1996) Interkinetic and migratory behavior of a cohort of neocortical neurons arising in the early embryonic murine cerebral wall. J Neurosci 16:5762-76
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Takahashi, T; Nowakowski, R S; Caviness Jr, V S (1996) The leaving or Q fraction of the murine cerebral proliferative epithelium: a general model of neocortical neuronogenesis. J Neurosci 16:6183-96
Sekiguchi, M; Abe, H; Nagato, Y et al. (1996) The abnormal distribution of mossy fiber bundles and morphological abnormalities in hippocampal formation of dreher(J) (dr(J)/dr(J))mouse. Brain Res Dev Brain Res 92:31-8
Caviness Jr, V S; Takahashi, T; Nowakowski, R S (1995) Numbers, time and neocortical neuronogenesis: a general developmental and evolutionary model. Trends Neurosci 18:379-83
Takahashi, T; Nowakowski, R S; Caviness Jr, V S (1995) The cell cycle of the pseudostratified ventricular epithelium of the embryonic murine cerebral wall. J Neurosci 15:6046-57
Sekiguchi, M; Nowakowski, R S; Nagato, Y et al. (1995) Morphological abnormalities in the hippocampus of the weaver mutant mouse. Brain Res 696:262-7

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