GIGA-Neurosciences, University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium.
Max Planck Research Group for RNA Biology, Max Planck Institute for Molecular Biomedicine, Von-Esmarch-Strasse 54, 48149 Muenster, Germany; Cells-in-Motion Cluster of Excellence, University of Muenster, Albert-Schweitzer-Campus 1, 48129 Muenster, Germany.
Dev Cell. 2015 Dec 7;35(5):553-567. doi: 10.1016/j.devcel.2015.11.005.
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.
大脑皮层包含由不同谱系相关祖细胞依次产生的神经元层。在皮质发生的开始时，第一代祖细胞是顶端祖细胞（APs），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（IPs）切换到间接神经发生，这些祖细胞产生所有皮层层的投射神经元。虽然已经建立了 APs 和 IPs 之间的直接谱系关系，但控制它们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会触发内质网应激和未折叠蛋白反应（UPR），进一步损害 IPs 的产生，并导致小头畸形。此外，我们证明皮质祖细胞中 UPR 的逐渐下调充当生理信号，以扩增 IPs 并促进间接神经发生。因此，我们的发现揭示了 UPR 在哺乳动物大脑发育过程中对细胞命运获得的贡献。
