Nguyen Loc Dinh, Nguyen Ly Huong, Dao Dat Xuan, Hattori Tsuyoshi, Takarada-Iemata Mika, Ishii Hiroshi, Tamatani Takashi, Kawasaki Hiroshi, Shinmyo Yohei, Onoue Kenta, Yonemura Shigenobu, Zhang Jun, Miyake Masato, Oyadomari Seiichi, Mori Kazutoshi, Hori Osamu
Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan.
Department of Medical Neuroscience, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan.
iScience. 2025 May 2;28(6):112569. doi: 10.1016/j.isci.2025.112569. eCollection 2025 Jun 20.
Although the unfolded protein response (UPR) is activated during brain development, its roles remain unclear. Here, we report that deletion of activating transcription factor 6 (ATF6), consisting of ATF6α and ATF6β, in the developing brain caused microcephaly and neonatal death in mice. Analysis of Atf6a/Atf6b double conditional knockout (dcKO) brains revealed diverse neuronal phenotypes, such as reduced neurogenesis, increased cell death, impaired cortical layer formation, and axon projection defects. Furthermore, hypervasculature, glial defects, and neuroinflammation were observed in dcKO brains. Notably, hypervasculature was detected at E14.5, when endoplasmic reticulum (ER) stress was morphologically unclear, but the UPR was activated to a greater extent in dcKO brains. Expression profiles revealed reduced levels of molecular chaperones in the ER and enhanced levels of PERK- and IRE1-downstream molecules, including VEGFA, in dcKO brains. Administration of a chemical chaperone 4-phenylbutyric acid partially rescued dcKO mice, suggesting roles of ATF6 for improving proteostasis and for coordinating the UPR.
尽管未折叠蛋白反应（UPR）在大脑发育过程中被激活，但其作用仍不清楚。在此，我们报告在发育中的大脑中缺失由激活转录因子6（ATF6）的α和β亚基组成的ATF6，会导致小鼠小头畸形和新生儿死亡。对Atf6a/Atf6b双条件敲除（dcKO）小鼠大脑的分析揭示了多种神经元表型，如神经发生减少、细胞死亡增加、皮质层形成受损以及轴突投射缺陷。此外，在dcKO小鼠大脑中观察到血管增生、胶质细胞缺陷和神经炎症。值得注意的是，在胚胎第14.5天（E14.5）就检测到血管增生，此时内质网（ER）应激在形态上并不明显，但dcKO小鼠大脑中的UPR被更大程度地激活。表达谱显示，dcKO小鼠大脑中内质网分子伴侣水平降低，而包括血管内皮生长因子A（VEGFA）在内的蛋白激酶R样内质网激酶（PERK）和肌醇需求酶1（IRE1）下游分子水平升高。给予化学伴侣4-苯基丁酸可部分挽救dcKO小鼠，这表明ATF6在改善蛋白质稳态和协调UPR方面发挥作用。
