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. 1998 Feb 3;95(3):1242-6.
doi: 10.1073/pnas.95.3.1242.

Changes in cell-cycle kinetics during the development and evolution of primate neocortex

D R Kornack  1 , P Rakic
Affiliations

Changes in cell-cycle kinetics during the development and evolution of primate neocortex

D R Kornack et al. Proc Natl Acad Sci U S A. .

Abstract

The evolutionary expansion of neocortical size in mammals is particularly prominent in anthropoid primates (i.e., monkeys, apes, and humans) and reflects an increased number of cortical cells, yet the developmental basis for this increase remains undefined. Cortical cell production depends on the length of the cell-division cycle of progenitor cells during neurogenesis, which previously has been measured only in smaller-brained rodents. To investigate whether cortical expansion in primates reflects modification of cell-cycle kinetics, we determined cell-cycle length during neurogenesis in the proliferative cerebral ventricular zone of fetal rhesus monkeys, by using cumulative S-phase labeling with bromodeoxyuridine. Cell-cycle durations in monkeys were as much as 5 times longer than those reported in rodents. Nonetheless, substantially more total rounds of cell division elapsed during the prolonged neurogenetic period of the monkey cortex, providing a basis for increased cell production. Moreover, unlike the progressive slowing that occurs during cortical development in rodents, cell division accelerated during neurogenesis of the enlarged cortical layers in monkeys. These findings suggest that evolutionary modification of the duration and number of progenitor cell divisions contributed to both the expansion and laminar elaboration of the primate neocortex.

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Figures

Figure 1
Figure 1
The VZ of the medial occipital cerebral wall at E40 (A), E60 (B), and E80 (C), 30 min after a single injection of BrdUrd. BrdUrd-labeled cell nuclei are darkly stained, unlabeled nuclei are counterstained red, and counterstained M-phase cells (arrowheads) occupy the ventricular surface. In A the BrdUrd-labeled cells above the primitive plexiform layer (PPL) are at the cortical surface and are probably meningeal cells; such cells are not pictured in B and C because of the subsequent growth of the cerebral wall. Note the changes in thickness of the VZ with age. SZ, subventricular zone; V, cerebral ventricle; dashed lines, VZ/PPL border (A) or VZ/SZ border (B and C). (Bar = 20 μm.)
Figure 2
Figure 2
Changes in LIs of monkey VZ with cumulative BrdUrd labeling at E40, E60, and E80. For each age, each survival time point (0.5 and 2.5 hr) is represented by two fetuses from two different mothers. Each data point is the mean LI of four nonconsecutive sections from a single brain. The SEM (not shown) of the mean LI of each brain is <8% at E40 and <5% at E60 and E80. [Note the closeness of the LI values (0.183 and 0.187) at E80 of the two fetuses at t = 0.5 hr, and of the two fetuses at t = 2.5 hr (0.256 and 0.260).]
Figure 3
Figure 3
Developmental profile of the lengths of the cell cycle (Tc) and S phase (Ts) during cortical neurogenesis in monkey VZ. The values of Tc and Ts at each age were calculated from the slope and y intercept, respectively, of the least-squares regression lines in Fig. 2. The height of the open circles indicates Ts, and the distance between the open and filled circles at each age indicates the combined lengths of G1, G2, and M.
Figure 4
Figure 4
Comparison of the length of the cell cycle (Tc) between monkey and mouse during cortical neurogenesis. Tc is compared at the beginning of the first (early), middle, and last (late) third of the total period of neurogenesis, corresponding to E40, E60, and E80 in monkeys and E11, E13, and E15 in mice. These three stages correlate respectively to the onset of neurogenesis for layer VI, the end of layer VI/onset of layer V neurogenesis, and the end of layer IV/onset of layer III neurogenesis (8, 9). (A) Tc expressed in absolute time. (B) Tc expressed as a proportion of the duration of the total neurogenetic period, which is 60 days in monkeys and 6 days in mice. Data for mice are from ref. .
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