Impact of ATF6 deletion on the embryonic brain development

Although the unfolded protein response (UPR) is involved in brain development, its roles remain unclear. Here, we report that deletion of ATF6, a major branch of the UPR, 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 partly rescued phenotypes of dkKO mice, suggesting roles of ATF6 for improving proteostasis and for coordinating the UPR activation.