Impact of ATF6 deletion on the embryonic brain development
Loc Dinh Nguyen,
Ly Huong Nguyen,
Dat Xuan Dao,
Tsuyoshi Hattori,
Mika Takarada-Iemata,
Hiroshi Ishii,
Takashi Tamatani,
Hiroshi Kawasaki,
Yohei Shinmyo,
Kenta Onoue,
Shigenobu Yonemura,
Jun Zhang,
Masato Miyake,
Seiichi Oyadomari,
Kazutoshi Mori,
Osamu Hori
Affiliations
Loc Dinh Nguyen
Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
Ly Huong Nguyen
Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
Dat Xuan Dao
Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
Tsuyoshi Hattori
Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
Mika Takarada-Iemata
Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
Hiroshi Ishii
Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
Takashi Tamatani
Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
Hiroshi Kawasaki
Department of Medical Neuroscience, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
Yohei Shinmyo
Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Kenta Onoue
Laboratory for Ultrastructural Research, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo, Japan
Shigenobu Yonemura
Laboratory for Ultrastructural Research, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo, Japan; Department of Cell Biology, Tokushima University Graduate School of Medicine, Tokushima, Japan
Jun Zhang
Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
Masato Miyake
Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
Seiichi Oyadomari
Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
Kazutoshi Mori
Kyoto University Institute for Advanced Study, Kyoto, Japan
Osamu Hori
Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan; Corresponding author
Summary: 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.
