CIP2A deficiency promotes depression‐like behaviors in mice through inhibition of dendritic arborization

Article28 October 2022 Source DataTransparent process CIP2A deficiency promotes depression-like behaviors in mice through inhibition of dendritic arborization Wen-Ting Hu Wen-Ting Hu Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, China Contribution: Data curation, Methodology, Writing - original draft Search for more papers by this author Zhen-Yu Liuyang Zhen-Yu Liuyang Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China Contribution: ​Investigation, Methodology Search for more papers by this author Yuan Tian Yuan Tian orcid.org/0000-0003-2941-7961 Department of Biology, Boston University, Boston, USA Contribution: Methodology Search for more papers by this author Jia-Wei Liang Jia-Wei Liang Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Contribution: Methodology Search for more papers by this author Xiao-Lin Zhang Xiao-Lin Zhang Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Contribution: Methodology Search for more papers by this author Hui-Liang Zhang Hui-Liang Zhang Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Contribution: Methodology Search for more papers by this author Guan Wang Guan Wang orcid.org/0000-0002-4806-3161 Department of Biology, Boston University, Boston, USA Contribution: Methodology Search for more papers by this author Yuda Huo Yuda Huo Department of Biology, Boston University, Boston, USA Contribution: Methodology Search for more papers by this author Yang-Ping Shentu Yang-Ping Shentu Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China Contribution: Resources Search for more papers by this author Jian-Zhi Wang Jian-Zhi Wang Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Contribution: Resources Search for more papers by this author Xiao-Chuan Wang Xiao-Chuan Wang orcid.org/0000-0001-8207-0042 Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Contribution: Resources Search for more papers by this author You-ming Lu You-ming Lu Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China The Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China Contribution: Resources Search for more papers by this author Jukka Westermarck Jukka Westermarck orcid.org/0000-0001-7478-3018 Turku Bioscience Centre, University of Turku, Turku, Finland Åbo Akademi University, Turku, Finland Institute of Biomedicine, University of Turku, Turku, Finland Contribution: Writing - review & editing Search for more papers by this author Heng-Ye Man Corresponding Author Heng-Ye Man [email protected] orcid.org/0000-0002-3530-3066 Department of Biology, Boston University, Boston, USA Contribution: Writing - review & editing Search for more papers by this author Rong Liu Corresponding Author Rong Liu [email protected] orcid.org/0000-0001-7477-6520 Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China The Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Contribution: Resources, Project administration, Writing - review & editing Search for more papers by this author Wen-Ting Hu Wen-Ting Hu Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, China Contribution: Data curation, Methodology, Writing - original draft Search for more papers by this author Zhen-Yu Liuyang Zhen-Yu Liuyang Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China Contribution: ​Investigation, Methodology Search for more papers by this author Yuan Tian Yuan Tian orcid.org/0000-0003-2941-7961 Department of Biology, Boston University, Boston, USA Contribution: Methodology Search for more papers by this author Jia-Wei Liang Jia-Wei Liang Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Contribution: Methodology Search for more papers by this author Xiao-Lin Zhang Xiao-Lin Zhang Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Contribution: Methodology Search for more papers by this author Hui-Liang Zhang Hui-Liang Zhang Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Contribution: Methodology Search for more papers by this author Guan Wang Guan Wang orcid.org/0000-0002-4806-3161 Department of Biology, Boston University, Boston, USA Contribution: Methodology Search for more papers by this author Yuda Huo Yuda Huo Department of Biology, Boston University, Boston, USA Contribution: Methodology Search for more papers by this author Yang-Ping Shentu Yang-Ping Shentu Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China Contribution: Resources Search for more papers by this author Jian-Zhi Wang Jian-Zhi Wang Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Contribution: Resources Search for more papers by this author Xiao-Chuan Wang Xiao-Chuan Wang orcid.org/0000-0001-8207-0042 Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Contribution: Resources Search for more papers by this author You-ming Lu You-ming Lu Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China The Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China Contribution: Resources Search for more papers by this author Jukka Westermarck Jukka Westermarck orcid.org/0000-0001-7478-3018 Turku Bioscience Centre, University of Turku, Turku, Finland Åbo Akademi University, Turku, Finland Institute of Biomedicine, University of Turku, Turku, Finland Contribution: Writing - review & editing Search for more papers by this author Heng-Ye Man Corresponding Author Heng-Ye Man [email protected] orcid.org/0000-0002-3530-3066 Department of Biology, Boston University, Boston, USA Contribution: Writing - review & editing Search for more papers by this author Rong Liu Corresponding Author Rong Liu [email protected] orcid.org/0000-0001-7477-6520 Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China The Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Contribution: Resources, Project administration, Writing - review & editing Search for more papers by this author Author Information Wen-Ting Hu1,2,†, Zhen-Yu Liuyang1,3,†, Yuan Tian4, Jia-Wei Liang1, Xiao-Lin Zhang1, Hui-Liang Zhang1, Guan Wang4, Yuda Huo4, Yang-Ping Shentu5, Jian-Zhi Wang1, Xiao-Chuan Wang1, You-ming Lu1,6, Jukka Westermarck7,8,9, Heng-Ye Man *,4 and Rong Liu *,1,6,10 1Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 2Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, China 3Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China 4Department of Biology, Boston University, Boston, USA 5Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China 6The Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China 7Turku Bioscience Centre, University of Turku, Turku, Finland 8Åbo Akademi University, Turku, Finland 9Institute of Biomedicine, University of Turku, Turku, Finland 10Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China † These authors contributed equally to this work *Corresponding author. Tel:+86 27 83692625; E-mail: [email protected] *Corresponding author. Tel: +1 617 358 4284; E-mail: [email protected] EMBO Reports (2022)23:e54911https://doi.org/10.15252/embr.202254911 Full textView the full text of the articlePDFDownload PDF of article text and main figures.PDF PLUSDownload PDF of article text, main figures, expanded view figures and appendix. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions Figures & Info Abstract Major depressive disorder (MDD) is a severe mental illness. Decreased brain plasticity and dendritic fields have been consistently found in MDD patients and animal models; however, the underlying molecular mechanisms remain to be clarified. Here, we demonstrate that the deletion of cancerous inhibitor of PP2A (CIP2A), an endogenous inhibitor of protein phosphatase 2A (PP2A), leads to depression-like behaviors in mice. Hippocampal RNA sequencing analysis of CIP2A knockout mice shows alterations in the PI3K-AKT pathway and central nervous system development. In primary neurons, CIP2A stimulates AKT activity and promotes dendritic development. Further analysis reveals that the effect of CIP2A in promoting dendritic development is dependent on PP2A-AKT signaling. In vivo, CIP2A deficiency-induced depression-like behaviors and impaired dendritic arborization are rescued by AKT activation. Decreased CIP2A expression and impaired dendrite branching are observed in a mouse model of chronic unpredictable mild stress (CUMS). Indicative of clinical relevance to humans, CIP2A expression is found decreased in transcriptomes from MDD patients. In conclusion, we discover a novel mechanism that CIP2A deficiency promotes depression through the regulation of PP2A-AKT signaling and dendritic arborization. Synopsis Mice deficient for the PP2A inhibitor CIP2A show reduced dendritic arborization and develop depression-like behaviors, which can be rescued by AKT activation. CIP2A deletion induces depression-like behaviors in mice. CIP2A promotes dendritic arborization and development through activating AKT. PP2A mediates the effects of CIP2A on AKT activation and dendritic development. CIP2A deficiency-induced depression-like behaviors and dendrite/spine loss are rescued by AKT activation in mice. CIP2A deficiency and impaired dendritic arborization coexist in brains of rat models of chronic mild stress-induced depression. Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 23,Issue 12,06 December 2022This month's cover highlights the article Cryo–EM structure of the octameric pore of Clostridium perfringens β–toxin by Julia Bruggisser, Ioan Iacovache, Horst Posthaus, Benoît Zuber and colleagues. The cover shows two octameric pores of C. Perfringens β–toxin in a lipid bilayer. One pore is shown bound to its receptor CD31 while the second is shown as cut through at the edge of the membrane. Alternating protomers in the oligomer are shown in different shades of blue while for the receptor, which was model based on an AlphaFold prediction, alternating Ig domains are shown in different shades of yellow. (Scientific image by Ioan Iacovache and Julia Bruggisser. Illustration created in Blender (http://www.blender.org) using a phospholipid bilayer template by Dr. Joseph G. Manion (https://cgfigures.gumroad.com/l/eJzxj. Copyright (author or institute): Institute of Anatomy, University of Bern) Volume 23Issue 126 December 2022In this issue ReferencesRelatedDetailsLoading ...