Neurons of neocortical layers II-VI in the dorsomedial cortex of the mouse arise in the pseudostratified ventricular epithelium (PVE) through 11 cell cycles over the six embryonic days 11-17 (E11-E17). The present experiments measure the proportion of daughter cells that leave the cycle (quiescent or Q fraction or Q) during a single cell cycle and the complementary proportion that continues to proliferate (proliferative or P fraction or P; P ϭ 1 Ϫ Q). Q and P for the PVE become 0.5 in the course of the eighth cycle, occurring on E14, and Q rises to ϳ0.8 (and P falls to ϳ0.2) in the course of the 10th cycle occurring on E16. This indicates that early in neuronogenesis, neurons are produced relatively slowly and the PVE expands rapidly but that the reverse happens in the final phase of neuronogenesis. The present analysis completes a cycle of analyses that have determined the four fundamental parameters of cell proliferation: growth fraction, lengths of cell cycle, and phases Q and P. These parameters are the basis of a coherent neuronogenetic model that characterizes patterns of growth of the PVE and mathematically relates the size of the initial proliferative population to the neuronal population of the adult neocortex. Key words: neocortical neuronogenesis; cell cycle; proliferation; mouse; ventricular zoneThe neocortical histogenetic sequence is initiated with generations of neurons (neuronogenesis) in the pseudostratified ventricular epithelium (PVE) at the margin of the ventricular cavities

Cytogenesis is the critical determinant of the total number of neurons that contribute to the formation of the cerebral cortex and the rate at which the cells are produced. Two distinct cell populations constitute the proliferative population, a pseudostratified ventricular epithelium (PVE) lying within the ventricular zone (VZ) at the margin of the ventricle, and a secondary proliferative population that is intermixed with the PVE within the VZ but also is distributed through the overlying subventricular and intermediate zones of the cerebral wall. The present analysis, based upon cumulative S-phase labeling of the proliferative cells with 5-bromo-2′-deoxyuridine, is principally concerned with the PVE of the gestational-day-14 (E14) murine cerebral wall. It has immediate but also more far reaching general objectives. The most immediate objective, essential to the design and interpretation of later experiments, is to provide estimates of critical parameters of cytogenesis for the PVE. The growth fraction is virtually 100%. The lengths of the overall cell cycle, S-, G2+M-m, and G1-phases are 15.1 hr, 3.8 hr, 2 hr, and 9.3 hr, respectively. The PVE is homogeneous with respect to cell cycle length. For methodological considerations, these estimates are more accurate than estimates of the same parameters obtained in earlier analyses based upon S-phase labeling with tritiated thymidine. It is particularly with respect to a shorter length of S-phase determined here that the present values are different from those obtained with thymidine. At a more innovative level, the temporal and spatial resolution of nuclear movement made possible by the methods developed here will allow, in a way not previously attempted, a fine-grained tracking of nuclear movement as cells execute the successive stages of the cell cycle or exit the cycle subsequent to mitosis. Such observations are pertinent to our understanding of the regulatory mechanisms of neocortical histogenesis and the cell biological mechanisms that govern the proliferative cycle of the ventricular epithelium itself. It is known that the velocity of nuclear movement in the PVE is maximum in G2 (fourfold increase from S- phase) and minimum in M and early G1.(ABSTRACT TRUNCATED AT 400 WORDS)

The time of origin of neurons in the hippocampal region was determined in a series of rhesus monkeys, each of which had been exposed to a pulse of tritiated thymidine (3H-TdR) at a different time during ontogeny and sacrificed between the second and fifth month after birth. No heavily labeled cells were found in the hippocampal region of animals exposed to 3H-TdR before embryonic day 33 (E33). Exposure to 3H-TdR given at E36 labels a few neurons in the deepest layers of the entorhinal area, and 3H-TdR given at E38 labels a small number of neurons in all hippocampal subdivisions. Although the first neurons are generated almost simultaneously throughout the hippocampal region, the proliferation ceases at a different time in each subdivision. The last neurons destined for the entorhinal area and presubiculum are generated between E70 and E75, whereas the last parasubicular neurons are generated between E75 and E80. The production of neurons that form the subiculum ends about two weeks earlier, between E56 and E65. Within the hippocampus, genesis of pyramidal cells ends between E70 and E80 in area CA1, between E56 and E65 in area CA2, between E65 and E80 in area CA1, between E56 and E65 in area CA2, between E65 and E70 in area CA3, and between E75 and E80 in area CA4. In contrast, the genesis of granule cells of the fascia dentata is considerably prolonged. It continues throughout the second half of gestation, declines steadily in the course of the first postnatal month, and tapers off during the next 2 months. There is a distinct inside-to-outside spatiotemporal gradient in the parahippocampal formation and in the stratum pyramidale of both the subiculum and hippocampus. In contrast, the spatiotemporal pattern of granule cell origin in the dentate gyrus is outside-to-inside. Furthermore, granule cells generated between E36 and E80 are distributed in a distinct suprapyramidal-to-infrapyramidal gradient, whereas those generated at later ages are distributed evenly throughout the fascia dentata. Correlation of the present findings with histological data on hippocampal neurogenesis in the human brain demonstrates that the timing and sequence of developmental events as well as spatiotemporal gradients are similar in both primate species.