Nature Communications (Nov 2023)
GDF11 slows excitatory neuronal senescence and brain ageing by repressing p21
- Di-Xian Wang,
- Zhao-Jun Dong,
- Sui-Xin Deng,
- Ying-Ming Tian,
- Yu-Jie Xiao,
- Xinran Li,
- Xiao-Ru Ma,
- Liang Li,
- Pengxiao Li,
- Hui-Zhong Chang,
- Longqi Liu,
- Fan Wang,
- Yang Wu,
- Xiang Gao,
- Shuang-Shuang Zheng,
- Hui-Min Gu,
- Ya-Nan Zhang,
- Jian-Bin Wu,
- Fan Wu,
- Yonglin Peng,
- Xiao-Wen Zhang,
- Ren-Ya Zhan,
- Li-Xia Gao,
- Qiming Sun,
- Xing Guo,
- Xiao-Dong Zhao,
- Jian-Hong Luo,
- Ruhong Zhou,
- Lei Han,
- Yousheng Shu,
- Jing-Wei Zhao
Affiliations
- Di-Xian Wang
- Department of Pathology of Sir Run Run Shaw Hospital, and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine
- Zhao-Jun Dong
- Department of Pathology of Sir Run Run Shaw Hospital, and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine
- Sui-Xin Deng
- Department of Neurosurgery, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University
- Ying-Ming Tian
- BGI Research
- Yu-Jie Xiao
- Department of Neurosurgery, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University
- Xinran Li
- The Global Scientific and Technological Innovation Center and the MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University
- Xiao-Ru Ma
- Department of Pathology of Sir Run Run Shaw Hospital, and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine
- Liang Li
- Department of Neurosurgery, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University
- Pengxiao Li
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai; Center for Systems Biomedicine, Shanghai Jiao Tong University
- Hui-Zhong Chang
- BGI Research
- Longqi Liu
- BGI Research
- Fan Wang
- Department of Pathology of Sir Run Run Shaw Hospital, and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine
- Yang Wu
- Department of Pathology of Sir Run Run Shaw Hospital, and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine
- Xiang Gao
- Department of Pathology of Sir Run Run Shaw Hospital, and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine
- Shuang-Shuang Zheng
- Department of Pathology of Sir Run Run Shaw Hospital, and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine
- Hui-Min Gu
- Department of Pathology of Sir Run Run Shaw Hospital, and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine
- Ya-Nan Zhang
- Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University
- Jian-Bin Wu
- Department of Pathology of Sir Run Run Shaw Hospital, and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine
- Fan Wu
- Department of Neurosurgery, the First Affiliated Hospital, Zhejiang University School of Medicine
- Yonglin Peng
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai; Center for Systems Biomedicine, Shanghai Jiao Tong University
- Xiao-Wen Zhang
- Department of Pathology of Sir Run Run Shaw Hospital, and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine
- Ren-Ya Zhan
- Department of Neurosurgery, the First Affiliated Hospital, Zhejiang University School of Medicine
- Li-Xia Gao
- Department of Neurology of the Second Affiliated Hospital, Interdisciplinary Institute of Neuroscience and Technology, Zhejiang University School of Medicine
- Qiming Sun
- Department of Biochemistry, and Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine
- Xing Guo
- Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University
- Xiao-Dong Zhao
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai; Center for Systems Biomedicine, Shanghai Jiao Tong University
- Jian-Hong Luo
- Department of Neurobiology and Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University
- Ruhong Zhou
- Institute of Quantitative Biology, College of Life Sciences, Zhejiang University
- Lei Han
- BGI Research
- Yousheng Shu
- Department of Neurosurgery, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University
- Jing-Wei Zhao
- Department of Pathology of Sir Run Run Shaw Hospital, and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine
- DOI
- https://doi.org/10.1038/s41467-023-43292-1
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 24
Abstract
Abstract As a major neuron type in the brain, the excitatory neuron (EN) regulates the lifespan in C. elegans. How the EN acquires senescence, however, is unknown. Here, we show that growth differentiation factor 11 (GDF11) is predominantly expressed in the EN in the adult mouse, marmoset and human brain. In mice, selective knock-out of GDF11 in the post-mitotic EN shapes the brain ageing-related transcriptional profile, induces EN senescence and hyperexcitability, prunes their dendrites, impedes their synaptic input, impairs object recognition memory and shortens the lifespan, establishing a functional link between GDF11, brain ageing and cognition. In vitro GDF11 deletion causes cellular senescence in Neuro-2a cells. Mechanistically, GDF11 deletion induces neuronal senescence via Smad2-induced transcription of the pro-senescence factor p21. This work indicates that endogenous GDF11 acts as a brake on EN senescence and brain ageing.
