The timetable of laminar neurogenesis contributes to the specification of cortical areas in mouse isocortex

Abstract

In the primate visual cortex, the birthdate of neurons in homologous layers differ on either side of the 17-18 border suggesting that there might be different timetables of laminar histogenesis in these two areas (Dehay et al. [1993] Nature 366:464-466 and Kennedy et al. [1996] Soc. Neurosci. Abst. 22:525). Because of the potential importance of these findings for understanding mechanisms that generate areal identity, we have developed an experimental approach that makes it possible to accurately compute the timetable of laminar histogenesis from birthdating experiments. Here we report the results of an exhaustive examination of the tempo of layer production in five cortical areas of the mouse. Tritiated thymidine pulse injections were made during embryonic development and labeled neurons were examined in three frontoparietal areas (areas 3, 4, and 6) and two occipital areas (areas 17 and 18a) of the adult cortex. The correlation between the radial distribution of neurons and the intensities of labeling enabled us to reliably identify first generation neurons (i.e., those neurons that quit the cell-cycle in the first round of mitosis after injection). For each cortical layer, the percentage of first generation neurons with respect to the total number of neurons defined a laminar labeling index. Changes of the laminar labeling index over time determined the timetable of layer formation. The onset and duration of layer formation was identical in the two occipital areas. This finding contrasted with the frontoparietal areas where there were important differences in the timing of infragranular and granular layer formation and noticeably production of layers VIa, V, and IV occurs earlier in area 3 than in area 6. The timing of laminar production of areas 17 and 18a resembles more that of area 3 than that of area 6. With respect to areas 3 and 6, area 4 shows an intermediate but significantly different timetable of layer production. These marked areal differences in the timetable of laminar histogenesis contrasted with the relative homogeneity within areas so that we have been able to demonstrate that the interareal differences are not merely the expression of known neurogenic gradients. These results suggest that in the mouse frontoparietal isocortex, neighbouring regions of the ventricular zone that will give rise to distinct areas follow distinct programs of layer production. These areal differences occur before thalamic innervation and suggest an early regionalisation of laminar histogenesis.

Tbr1andFezf2Regulate Alternate Corticofugal Neuronal Identities during Neocortical Development

“…During murine cortical neurogenesis, layer 6 corticothalamic neurons start to be generated at E11.5 and reach their neurogenic peak at E12.5, while layer 5 neurogenesis peaks 24 hours later (Polleux et al, 1997, 1998). To test whether the increased numbers of CTIP2 high neurons in the Tbr1 −/− mice originated from mis-specified corticothalamic neurons, we performed BrdU birthdating to identify the embryonic ages during which the CTIP2 high neurons were generated.…”

Evo-Devo and the Primate Isocortex: The Central Organizing Role of Intrinsic Gradients of Neurogenesis

“…In some species, the difference in terminal neurogenesis between the rostral and caudal pole varies at most by a few days whereas in other species, the difference in terminal neurogenesis occurs for over more than two weeks. For instance, in mice, neurogenesis starts around ED 11 throughout the presumptive isocortex and terminal neurogenesis in the rostral and caudal pole lasts approximately six to eight days [Polleux et al, 1997]. In the rhesus monkey ( Macaca mullatta ), neurons exit the cell cycle on approximately embryonic day (ED) 38 throughout the isocortex.…”

“…For instance, in monkeys, there is a center-to peripheral gradient in neurogenesis timing in the developing retina and a rostro-caudal (a.k.a anterior to posterior) gradient in neurogenesis timing in the presumptive isocortex [Finlay, 2008; Rakic, 2002], which is less pronounced in rodents [Polleux et al, 1997; Nowakowski et al, 2002; Finlay et al, 2005; Suter et al, 2007]. Whether the emergence of spatiotemporal gradients within structures is latent in the mechanism that produces a given structure in a small brain and is simply revealed in a larger brain, or whether spatiotemporal gradients evolve independently of other spatiotemporal gradients does not appear to have a specific answer.…”

Simulating Cortical Development as a Self Constructing Process: A Novel Multi-Scale Approach Combining Molecular and Physical Aspects

“…[10]) that a stopping mechanism due to contact with L1 is sufficient if the neuron precursors are really produced in distinct separate waves (first all the L6 cells, then all the L5 cells etc.). However our current GRN, as seems to be the case in biology [42], generates the different cell types with a certain degree of overlap. If the hypothesis of overlapping production phases holds, a stopping signal expressed only at the border of L1 is not sufficient to provide correct lamination, since later born cells belonging to deep layers could pass by earlier born cells belonging to more superficial layers.…”