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Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways

Author

Listed:
  • Won-Suk Chung

    (Stanford University, School of Medicine)

  • Laura E. Clarke

    (Stanford University, School of Medicine)

  • Gordon X. Wang

    (Stanford University, School of Medicine)

  • Benjamin K. Stafford

    (University of Michigan)

  • Alexander Sher

    (University of California)

  • Chandrani Chakraborty

    (Stanford University, School of Medicine)

  • Julia Joung

    (Stanford University, School of Medicine)

  • Lynette C. Foo

    (Institute of Molecular and Cell Biology, A *Star, 61 Biopolis Drive, Proteos Building, 138673 Singapore)

  • Andrew Thompson

    (Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, CLS12250, Boston, Massachusetts 02115, USA)

  • Chinfei Chen

    (Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, CLS12250, Boston, Massachusetts 02115, USA)

  • Stephen J. Smith

    (Stanford University, School of Medicine)

  • Ben A. Barres

    (Stanford University, School of Medicine)

Abstract

To achieve its precise neural connectivity, the developing mammalian nervous system undergoes extensive activity-dependent synapse remodelling. Recently, microglial cells have been shown to be responsible for a portion of synaptic pruning, but the remaining mechanisms remain unknown. Here we report a new role for astrocytes in actively engulfing central nervous system synapses. This process helps to mediate synapse elimination, requires the MEGF10 and MERTK phagocytic pathways, and is strongly dependent on neuronal activity. Developing mice deficient in both astrocyte pathways fail to refine their retinogeniculate connections normally and retain excess functional synapses. Finally, we show that in the adult mouse brain, astrocytes continuously engulf both excitatory and inhibitory synapses. These studies reveal a novel role for astrocytes in mediating synapse elimination in the developing and adult brain, identify MEGF10 and MERTK as critical proteins in the synapse remodelling underlying neural circuit refinement, and have important implications for understanding learning and memory as well as neurological disease processes.

Suggested Citation

  • Won-Suk Chung & Laura E. Clarke & Gordon X. Wang & Benjamin K. Stafford & Alexander Sher & Chandrani Chakraborty & Julia Joung & Lynette C. Foo & Andrew Thompson & Chinfei Chen & Stephen J. Smith & Be, 2013. "Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways," Nature, Nature, vol. 504(7480), pages 394-400, December.
    • Handle: RePEc:nat:nature:v:504:y:2013:i:7480:d:10.1038_nature12776
    DOI: 10.1038/nature12776
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    Citations

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    Cited by:

    1. Hidenori Tabata & Megumi Sasaki & Masakazu Agetsuma & Hitomi Sano & Yuki Hirota & Michio Miyajima & Kanehiro Hayashi & Takao Honda & Masashi Nishikawa & Yutaka Inaguma & Hidenori Ito & Hirohide Takeba, 2022. "Erratic and blood vessel-guided migration of astrocyte progenitors in the cerebral cortex," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    2. Xiaojing Shi & Longlong Luo & Jixian Wang & Hui Shen & Yongfang Li & Muyassar Mamtilahun & Chang Liu & Rubing Shi & Joon-Hyuk Lee & Hengli Tian & Zhijun Zhang & Yongting Wang & Won-Suk Chung & Yaohui , 2021. "Stroke subtype-dependent synapse elimination by reactive gliosis in mice," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    3. Ikuko Takeda & Kohei Yoshihara & Dennis L. Cheung & Tomoko Kobayashi & Masakazu Agetsuma & Makoto Tsuda & Kei Eto & Schuichi Koizumi & Hiroaki Wake & Andrew J. Moorhouse & Junichi Nabekura, 2022. "Controlled activation of cortical astrocytes modulates neuropathic pain-like behaviour," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Samuel S. Kim & Buu Truong & Karthik Jagadeesh & Kushal K. Dey & Amber Z. Shen & Soumya Raychaudhuri & Manolis Kellis & Alkes L. Price, 2024. "Leveraging single-cell ATAC-seq and RNA-seq to identify disease-critical fetal and adult brain cell types," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    5. Danyang Chen & Qianqian Lou & Xiang-Jie Song & Fang Kang & An Liu & Changjian Zheng & Yanhua Li & Di Wang & Sen Qun & Zhi Zhang & Peng Cao & Yan Jin, 2024. "Microglia govern the extinction of acute stress-induced anxiety-like behaviors in male mice," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    6. Johnna Doherty & Amy E Sheehan & Rachel Bradshaw & A Nicole Fox & Tsai-Yi Lu & Marc R Freeman, 2014. "PI3K Signaling and Stat92E Converge to Modulate Glial Responsiveness to Axonal Injury," PLOS Biology, Public Library of Science, vol. 12(11), pages 1-16, November.
    7. Ting Wan & Wusheng Zhu & Ying Zhao & Xiaohao Zhang & Ruidong Ye & Meng Zuo & Pengfei Xu & Zhenqian Huang & Chunni Zhang & Yi Xie & Xinfeng Liu, 2022. "Astrocytic phagocytosis contributes to demyelination after focal cortical ischemia in mice," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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