Institut Jacques Monod, CNRS UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, 15 Rue Hélène Brion , 75205Paris Cedex, France.
Institut Jacques Monod, CNRS UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, 15 Rue Hélène Brion, 75205 Paris Cedex, France.
Cereb Cortex. 2017 Oct 1;27(10):4701-4718. doi: 10.1093/cercor/bhw264.
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.
大脑皮层神经元的丧失通常被认为会导致脑体积的最终减少。然而，对于发育中的大脑皮层如何应对早期出生神经元的死亡，人们知之甚少。在这里，我们利用一种转基因小鼠模型来解决这个问题，在该模型中，从早期胚胎阶段到皮质发生中期，大量的细胞凋亡发生在有丝分裂后区。出乎意料的是，由于 E14.5 时上层神经元的过度产生，E18.5 时突变皮质板的厚度是正常的。我们开发并模拟了一个数学模型来从理论上研究系统的恢复能力，发现中间祖细胞（IPs）的有丝分裂分裂概率的微小增加是一个强大的补偿杠杆。我们通过实验证实，突变小鼠显示出更多的脑室下祖细胞，包括基底放射状胶质样细胞和 IPs。后者显示出增殖率增加、Pax6 表达持续时间延长和细胞周期持续时间缩短。总之，这些结果表明，新皮层祖细胞具有显著的可塑性，可以通过调节脑室下分裂来适应主要的胚胎损伤，从而确保产生适当数量的神经元。
