Regulation of Neuroblast Cell-Cycle Kinetics Plays a Crucial Role in the Generation of Unique Features of Neocortical Areas

Abstract

Cortical neurons are generated in the germinal zones lining the ventricles before migrating predominantly radially. To investigate regional differences in the cell-cycle kinetics of neuroblasts, pulse [ 3 H]-thymidine injections were made throughout corticogenesis, and labeled neuron counts were compared in areas 3, 6, 17, and 18a in the adult mouse. The relationship between height in the cortex and intensity of autoradiographic signal distinguishes first generation and subsequent generations of neurons. This provides the mitotic history of defined sets of neurons and is a powerful tool for analyzing areal differences in cell-cycle kinetics. The infragranular laminar labeling indices of different generations show significant differences in areas 3 and 6. The labeling index of first generation neurons shows that the rate of neuron production is higher in area 3 than in area 6. This increased generation rate in area 3 was accompanied by two major changes. First, computation of the labeling index of the subsequent generation neurons (which reflects percentages of precursors in S-phase at the moment of the pulse) indicates a shorter cell cycle in area 3. Second, the total population of labeled neurons contains a higher proportion of first generation neurons in area 3, implying a higher leaving fraction in this area. Computer simulations of these areal differences of cell-cycle kinetics generate neuron numbers that are in close agreement with published data. Altogether these findings reveal an early regionalization of the ventricular zone that serves to generate unique features of future cortical areas.

Cortical development: the art of generating cell diversity

“…Surprisingly, the OSVZ contains cells with a radial glia morphology, which is notably distinct from the morphology of the precursors in the SVZ of the mouse cortex that exhibit only short processes with no apparent contact with the apical surface or basement membrane Miyata et al, 2004;Noctor et al, 2004). Importantly for the generation of area-specific differences, precursors in the OSVZ of V1 in the primate cortex have a 30% faster cell cycle than those located in V2 [for cell cycle differences in cortical area of the mouse, see Polleux et al (Polleux et al, 1997)], and the fastest cycling cells are located in close proximity to thalamic axons that innervate V1 but not V2. These findings suggest that shortening the cell cycle in G1 by decreasing p27 levels and increasing cyclin E causes the area-specific increase in upper layer neurons mediated by the innervating afferents.…”

Cell-Cycle Kinetics of Neocortical Precursors Are Influenced by Embryonic Thalamic Axons

“…Environmental signaling during the final round of mitosis has been shown to be a key event in the specification of the future connectivity of cortical neuroblasts (McConnell and Kaznowski, 1991;Eagleson et al, 1997), and modulation of cell-cycle kinetics contributes to determining areal cytoarchitecture (Dehay et al, 1993;Polleux et al, 1997). There is indirect evidence that, in the primate, thalamic afferents contribute toward specifying the identity of cortical areas during very early stages of cortical development by regulating the rates of neurogenesis in the ventricular zone (Dehay et al, 1993.…”

“…Regionalization of cell-cycle kinetics in the ventricular zone plays a determinant role in the generation of cytoarchitecturally distinct neocortical areas characterized by different numbers of neurons per unit area of cortical surface (Dehay et al, 1993;Polleux et al, 1997), and increased rates of proliferation are characteristic of precursors of areas containing high numbers of neurons (Dehay et al, 1993;Polleux et al, 1997Polleux et al, , 1998. Note that the increase in proliferation rates that are characteristic of A17 precursors in the primate visual cortex is observed at a stage when thalamic axons are in close proximity to the germinal zones (Dehay et al, 1993).…”

Molecular Evidence for the Early Specification of Presumptive Functional Domains in the Embryonic Primate Cerebral Cortex

“…This protomap would initially direct associations among neighboring cortical cells, and it later attracts appropriate inputs, with intrinsic and extrinsic forces collaborating in the final assignment of region-specific properties (Rakic, 1988). In support of this concept, domain-specific molecular markers as well as regional differences in rates of cell division suggest that distinct populations of cells exist within the cerebral cortex (Barbe and Levitt, 1991;Arimatsu et al, 1992;Dehay et al, 1993;CohenTannoudji et al, 1994;Bulfone et al, 1995;Eagleson et al, 1997;Polleux et al, 1997;Na et al, 1998;Nothias et al, 1998). Furthermore, tissue culture, cell lineage, and transplantation studies testify that cortical cells exhibit certain phenotypic, laminar, and regional biases (Luskin et al, 1988;McConnell, 1988;Parnavelas et al, 1991;Ferri and Levitt, 1993;Tan et al, 1998).…”