Impact of ATF6 deletion on the embryonic brain development
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. Ana...
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| Language: | English |
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Elsevier
2025-06-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225008302 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Loc Dinh Nguyen |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9549806bfcc84fc08019eedac825fa39 |
| institution | DOAJ |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-9549806bfcc84fc08019eedac825fa392025-08-20T03:10:31ZengElsevieriScience2589-00422025-06-0128611256910.1016/j.isci.2025.112569Impact of ATF6 deletion on the embryonic brain developmentLoc Dinh Nguyen0Ly Huong Nguyen1Dat Xuan Dao2Tsuyoshi Hattori3Mika Takarada-Iemata4Hiroshi Ishii5Takashi Tamatani6Hiroshi Kawasaki7Yohei Shinmyo8Kenta Onoue9Shigenobu Yonemura10Jun Zhang11Masato Miyake12Seiichi Oyadomari13Kazutoshi Mori14Osamu Hori15Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, JapanDepartment of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, JapanDepartment of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, JapanDepartment of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, JapanDepartment of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, JapanDepartment of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, JapanDepartment of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, JapanDepartment of Medical Neuroscience, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, JapanDepartment of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, JapanLaboratory for Ultrastructural Research, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo, JapanLaboratory for Ultrastructural Research, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo, Japan; Department of Cell Biology, Tokushima University Graduate School of Medicine, Tokushima, JapanDivision of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, JapanDivision of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, JapanDivision of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, JapanKyoto University Institute for Advanced Study, Kyoto, JapanDepartment of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004225008302NeuroscienceCell biologyDevelopmental biology |
| spellingShingle | 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 Impact of ATF6 deletion on the embryonic brain development iScience Neuroscience Cell biology Developmental biology |
| title | Impact of ATF6 deletion on the embryonic brain development |
| title_full | Impact of ATF6 deletion on the embryonic brain development |
| title_fullStr | Impact of ATF6 deletion on the embryonic brain development |
| title_full_unstemmed | Impact of ATF6 deletion on the embryonic brain development |
| title_short | Impact of ATF6 deletion on the embryonic brain development |
| title_sort | impact of atf6 deletion on the embryonic brain development |
| topic | Neuroscience Cell biology Developmental biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225008302 |
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