Site-directed MT1-MMP trafficking and surface insertion regulate achr clustering and remodeling at developing NMJS

Zora Chui Kuen Chan; Hiu Lam Rachel Kwan; Yin Shun Wong; Zhixin Jiang; Zhongjun Zhou; Kin Wai Tam; Ying Shing Chan; Chi Bun Chan; Chi Wai Lee

doi:10.7554/eLife.54379

Site-directed MT1-MMP trafficking and surface insertion regulate achr clustering and remodeling at developing NMJS

Zora Chui Kuen Chan, Hiu Lam Rachel Kwan, Yin Shun Wong, Zhixin Jiang, Zhongjun Zhou, Kin Wai Tam, Ying Shing Chan, Chi Bun Chan, Chi Wai Lee^*

^*Corresponding author for this work

Department of Biology

Research output: Contribution to journal › Journal article › peer-review

22 Citations (Scopus)

Abstract

At vertebrate neuromuscular junctions (NMJs), the synaptic basal lamina contains different extracellular matrix (ECM) proteins and synaptogenic factors that induce and maintain synaptic specializations. Here, we report that podosome-like structures (PLSs) induced by ubiquitous ECM proteins regulate the formation and remodeling of acetylcholine receptor (AChR) clusters via focal ECM degradation. Mechanistically, ECM degradation is mediated by PLS-directed trafficking and surface insertion of membrane-type 1 matrix metalloproteinase (MT1-MMP) to AChR clusters through microtubule-capturing mechanisms. Upon synaptic induction, MT1-MMP plays a crucial role in the recruitment of aneural AChR clusters for the assembly of postsynaptic specializations. Lastly, the structural defects of NMJs in embryonic MT1-MMP^-/- mice further demonstrate the physiological role of MT1-MMP in normal NMJ development. Collectively, this study suggests that postsynaptic MT1-MMP serves as a molecular switch to synaptogenesis by modulating local ECM environment for the deposition of synaptogenic signals that regulate postsynaptic differentiation at developing NMJs.

Original language	English
Article number	e54379
Number of pages	33
Journal	eLife
Volume	9
DOIs	https://doi.org/10.7554/eLife.54379
Publication status	Published - 24 Mar 2020

Scopus Subject Areas

General Neuroscience
General Immunology and Microbiology
General Biochemistry,Genetics and Molecular Biology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.7554/eLife.54379

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@article{1dbd22a7f3ae480ca14bc5cd8921ba13,

title = "Site-directed MT1-MMP trafficking and surface insertion regulate achr clustering and remodeling at developing NMJS",

abstract = "At vertebrate neuromuscular junctions (NMJs), the synaptic basal lamina contains different extracellular matrix (ECM) proteins and synaptogenic factors that induce and maintain synaptic specializations. Here, we report that podosome-like structures (PLSs) induced by ubiquitous ECM proteins regulate the formation and remodeling of acetylcholine receptor (AChR) clusters via focal ECM degradation. Mechanistically, ECM degradation is mediated by PLS-directed trafficking and surface insertion of membrane-type 1 matrix metalloproteinase (MT1-MMP) to AChR clusters through microtubule-capturing mechanisms. Upon synaptic induction, MT1-MMP plays a crucial role in the recruitment of aneural AChR clusters for the assembly of postsynaptic specializations. Lastly, the structural defects of NMJs in embryonic MT1-MMP-/- mice further demonstrate the physiological role of MT1-MMP in normal NMJ development. Collectively, this study suggests that postsynaptic MT1-MMP serves as a molecular switch to synaptogenesis by modulating local ECM environment for the deposition of synaptogenic signals that regulate postsynaptic differentiation at developing NMJs.",

author = "Chan, {Zora Chui Kuen} and Kwan, {Hiu Lam Rachel} and Wong, {Yin Shun} and Zhixin Jiang and Zhongjun Zhou and Tam, {Kin Wai} and Chan, {Ying Shing} and Chan, {Chi Bun} and Lee, {Chi Wai}",

note = "This project was partly supported by the Early Career Grant (27102316) and General Research Fund (17100718 and 17100219) from Research Grants Council of Hong Kong, the Health and Medical Research Fund (04151086) from Food and Health Bureau of Hong Kong, and the Seed Fund Programme for Basic Research from The University of Hong Kong (201601159003, 201711159098, and 201811159078) to CWL. HRK is partly supported by HKU Postgraduate Fellowships in Integrative Medicine. We thank Dr Weichun Lin (UT Southwestern) for sharing the whole-mount diaphragm staining protocol, and Dr Timothy Gomez (University of Wisconsin-Madison) for providing the MT1-MMP antibody. Publisher Copyright: {\textcopyright} Chan et al.",

year = "2020",

month = mar,

day = "24",

doi = "10.7554/eLife.54379",

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volume = "9",

journal = "eLife",

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TY - JOUR

T1 - Site-directed MT1-MMP trafficking and surface insertion regulate achr clustering and remodeling at developing NMJS

AU - Chan, Zora Chui Kuen

AU - Kwan, Hiu Lam Rachel

AU - Wong, Yin Shun

AU - Jiang, Zhixin

AU - Zhou, Zhongjun

AU - Tam, Kin Wai

AU - Chan, Ying Shing

AU - Chan, Chi Bun

AU - Lee, Chi Wai

N1 - This project was partly supported by the Early Career Grant (27102316) and General Research Fund (17100718 and 17100219) from Research Grants Council of Hong Kong, the Health and Medical Research Fund (04151086) from Food and Health Bureau of Hong Kong, and the Seed Fund Programme for Basic Research from The University of Hong Kong (201601159003, 201711159098, and 201811159078) to CWL. HRK is partly supported by HKU Postgraduate Fellowships in Integrative Medicine. We thank Dr Weichun Lin (UT Southwestern) for sharing the whole-mount diaphragm staining protocol, and Dr Timothy Gomez (University of Wisconsin-Madison) for providing the MT1-MMP antibody. Publisher Copyright: © Chan et al.

PY - 2020/3/24

Y1 - 2020/3/24

N2 - At vertebrate neuromuscular junctions (NMJs), the synaptic basal lamina contains different extracellular matrix (ECM) proteins and synaptogenic factors that induce and maintain synaptic specializations. Here, we report that podosome-like structures (PLSs) induced by ubiquitous ECM proteins regulate the formation and remodeling of acetylcholine receptor (AChR) clusters via focal ECM degradation. Mechanistically, ECM degradation is mediated by PLS-directed trafficking and surface insertion of membrane-type 1 matrix metalloproteinase (MT1-MMP) to AChR clusters through microtubule-capturing mechanisms. Upon synaptic induction, MT1-MMP plays a crucial role in the recruitment of aneural AChR clusters for the assembly of postsynaptic specializations. Lastly, the structural defects of NMJs in embryonic MT1-MMP-/- mice further demonstrate the physiological role of MT1-MMP in normal NMJ development. Collectively, this study suggests that postsynaptic MT1-MMP serves as a molecular switch to synaptogenesis by modulating local ECM environment for the deposition of synaptogenic signals that regulate postsynaptic differentiation at developing NMJs.

AB - At vertebrate neuromuscular junctions (NMJs), the synaptic basal lamina contains different extracellular matrix (ECM) proteins and synaptogenic factors that induce and maintain synaptic specializations. Here, we report that podosome-like structures (PLSs) induced by ubiquitous ECM proteins regulate the formation and remodeling of acetylcholine receptor (AChR) clusters via focal ECM degradation. Mechanistically, ECM degradation is mediated by PLS-directed trafficking and surface insertion of membrane-type 1 matrix metalloproteinase (MT1-MMP) to AChR clusters through microtubule-capturing mechanisms. Upon synaptic induction, MT1-MMP plays a crucial role in the recruitment of aneural AChR clusters for the assembly of postsynaptic specializations. Lastly, the structural defects of NMJs in embryonic MT1-MMP-/- mice further demonstrate the physiological role of MT1-MMP in normal NMJ development. Collectively, this study suggests that postsynaptic MT1-MMP serves as a molecular switch to synaptogenesis by modulating local ECM environment for the deposition of synaptogenic signals that regulate postsynaptic differentiation at developing NMJs.

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SN - 2050-084X

VL - 9

JO - eLife

JF - eLife

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ER -

Site-directed MT1-MMP trafficking and surface insertion regulate achr clustering and remodeling at developing NMJS

Abstract

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