A dynamic unfolded protein response contributes to the control of cortical neurogenesis

The cerebral cortex contains layers of neurons sequentially generated by distinct lineage-related progenitors. At the onset of corticogenesis, the first-born progenitors are apical progenitors (APs) whose asymmetric division give birth directly to neurons. Later, they switch to indirect neurogenesis by generating intermediate progenitors (IPs), which give rise to projection neurons of all cortical layers. While a direct lineage relationship between APs and IPs has been established, the molecular mechanism that controls their transition remains elusive. Our data suggest that interfering with codon translation speed triggers endoplasmic reticulum stress and the unfolded protein response (UPR), further impairing the generation of IPs and leading to microcephaly. Moreover, we demonstrate that a progressive downregulation of UPR in cortical progenitors acts as physiological signal to amplify IPs and promotes indirect neurogenesis. Thus, our findings reveal a hitherto unrecognized contribution of UPR to cell fate acquisition during mammalian brain development. Ribosome profiling and RNA-Seq of forebrains from E14.5 mouse embryos from wild type animals and mutants carrying a conditional knockout of ELP3 in cortical progenitors大脑皮层由不同谱系相关的祖细胞依次产生的神经元层构成。在皮质发生起始阶段，首批生成的祖细胞为顶端祖细胞（apical progenitors, APs），其通过不对称分裂直接产生神经元。后续，它们转向间接神经发生模式，通过生成中间祖细胞（intermediate progenitors, IPs），再由后者分化为所有皮层层级的投射神经元。尽管顶端祖细胞与中间祖细胞间的直接谱系关联已得到证实，但调控二者转变的分子机制仍不明晰。我们的研究数据显示，干扰密码子翻译速度会触发内质网应激（endoplasmic reticulum stress）与未折叠蛋白反应（unfolded protein response, UPR），进而损害中间祖细胞的生成并引发小头畸形。此外，我们证实，皮层祖细胞中未折叠蛋白反应的渐进式下调可作为一种生理信号，扩增中间祖细胞群体并促进间接神经发生。综上，我们的研究发现揭示了未折叠蛋白反应在哺乳动物脑发育过程中对细胞命运获取的此前未被认知的重要贡献。本研究对野生型小鼠以及皮层祖细胞中携带ELP3条件性敲除的突变型E14.5小鼠胚胎的前脑开展了核糖体谱分析（ribosome profiling）与RNA测序（RNA-Seq）。