Enhanced Abventricular Proliferation Compensates Cell Death in the Embryonic Cerebral Cortex

Abstract

Loss of neurons in the neocortex is generally thought to result in a final reduction of cerebral volume. Yet, little is known on how the developing cerebral cortex copes with death of early-born neurons. Here, we tackled this issue by taking advantage of a transgenic mouse model in which, from early embryonic stages to mid-corticogenesis, abundant apoptosis is induced in the postmitotic compartment. Unexpectedly, the thickness of the mutant cortical plate at E18.5 was normal, due to an overproduction of upper layer neurons at E14.5. We developed and simulated a mathematical model to investigate theoretically the recovering capacity of the system and found that a minor increase in the probability of proliferative divisions of intermediate progenitors (IPs) is a powerful compensation lever. We confirmed experimentally that mutant mice showed an enhanced number of abventricular progenitors including basal radial glia-like cells and IPs. The latter displayed increased proliferation rate, sustained Pax6 expression and shorter cell cycle duration. Altogether, these results demonstrate the remarkable plasticity of neocortical progenitors to adapt to major embryonic insults via the modulation of abventricular divisions thereby ensuring the production of an appropriate number of neurons.

Keywords: abventricular proliferation; cell death; compensation; embryonic cerebral cortex; upper layer neurons.