A Dynamic Unfolded Protein Response Contributes to the Control of Cortical Neurogenesis
A Dynamic Unfolded Protein Response Contributes to the Control of Cortical Neurogenesis
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DOI：
10.1016/j.devcel.2015.11.005
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发表时间：
2015-12-07
影响因子：
11.8
通讯作者：
Nguyen, Laurent
中科院分区：
文献类型：
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作者：
Laguesse, Sophie;Creppe, Catherine;Nguyen, Laurent
大脑皮层包含由不同的谱系相关祖细胞顺序产生的神经元层。在皮质生成开始时，第一个出生的祖细胞是顶端祖细胞（AP），其不对称分裂直接产生神经元。后来，它们通过产生中间祖细胞（IP）转向间接神经发生，中间祖细胞产生所有皮质层的投射神经元。虽然已经建立了AP和IP之间的直接谱系关系，但控制其过渡的分子机制仍然难以捉摸。在这里，我们表明，干扰密码子翻译速度触发ER应激和未折叠蛋白反应（UPR），进一步削弱IP的产生，导致小头畸形。此外，我们证明，在皮质祖细胞中UPR的逐步下调作为一个生理信号，以放大IP和促进间接神经发生。因此，我们的研究结果揭示了在哺乳动物大脑发育过程中UPR对细胞命运获取的贡献。
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 gives 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. Here we show that interfering with codon translation speed triggers ER 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 a physiological signal to amplify IPs and promotes indirect neurogenesis. Thus, our findings reveal a contribution of UPR to cell fate acquisition during mammalian brain development.