2. Academic Validation
  3. Impact of ATF6 deletion on the embryonic brain development

Impact of ATF6 deletion on the embryonic brain development

  • iScience. 2025 May 2;28(6):112569. doi: 10.1016/j.isci.2025.112569.
Loc Dinh Nguyen 1,  Ly Huong Nguyen 1,  Dat Xuan Dao 1,  Tsuyoshi Hattori 1,  Mika Takarada-Iemata 1,  Hiroshi Ishii 1,  Takashi Tamatani 1,  Hiroshi Kawasaki 2,  Yohei Shinmyo 3,  Kenta Onoue 4,  Shigenobu Yonemura 4 5,  Jun Zhang 6,  Masato Miyake 6,  Seiichi Oyadomari 6,  Kazutoshi Mori 7,  Osamu Hori 1
Affiliations

Affiliations

  • 1 Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan.
  • 2 Department of Medical Neuroscience, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan.
  • 3 Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
  • 4 Laboratory for Ultrastructural Research, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo, Japan.
  • 5 Department of Cell Biology, Tokushima University Graduate School of Medicine, Tokushima, Japan.
  • 6 Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan.
  • 7 Kyoto University Institute for Advanced Study, Kyoto, Japan.
PMID: 40487428 DOI: 10.1016/j.isci.2025.112569
Abstract

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.

Keywords

Cell biology; Developmental biology; Neuroscience.

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