The ESCRT-III Protein CHMP1A Mediates Secretion of Sonic Hedgehog on a Distinctive Subtype of Extracellular Vesicles

Michael E. Coulter; Cristina M. Dorobantu; Gerrald A. Lodewijk; François Delalande; Sarah Cianferani; Vijay S. Ganesh; Richard S. Smith; Elaine T. Lim; C. Shan Xu; Song Pang; Eric T. Wong; Hart G.W. Lidov; Monica L. Calicchio; Edward Yang; Dilenny M. Gonzalez; Thorsten M. Schlaeger; Ganeshwaran H. Mochida; Harald Hess; Wei Chung Allen Lee; Maria K. Lehtinen; Tomas Kirchhausen; David Haussler; Frank M.J. Jacobs; Raphael Gaudin; Christopher A. Walsh

doi:10.1016/j.celrep.2018.06.100

The ESCRT-III Protein CHMP1A Mediates Secretion of Sonic Hedgehog on a Distinctive Subtype of Extracellular Vesicles

Michael E. Coulter, Cristina M. Dorobantu, Gerrald A. Lodewijk, François Delalande, Sarah Cianferani, Vijay S. Ganesh, Richard S. Smith, Elaine T. Lim, C. Shan Xu, Song Pang, Eric T. Wong, Hart G.W. Lidov, Monica L. Calicchio, Edward Yang, Dilenny M. Gonzalez, Thorsten M. Schlaeger, Ganeshwaran H. Mochida, Harald Hess, Wei Chung Allen Lee, Maria K. LehtinenTomas Kirchhausen, David Haussler, Frank M.J. Jacobs^*, Raphael Gaudin, Christopher A. Walsh

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

73 Scopus citations

Abstract

Endosomal sorting complex required for transport (ESCRT) complex proteins regulate biogenesis and release of extracellular vesicles (EVs), which enable cell-to-cell communication in the nervous system essential for development and adult function. We recently showed human loss-of-function (LOF) mutations in ESCRT-III member CHMP1A cause autosomal recessive microcephaly with pontocerebellar hypoplasia, but its mechanism was unclear. Here, we show Chmp1a is required for progenitor proliferation in mouse cortex and cerebellum and progenitor maintenance in human cerebral organoids. In Chmp1a null mice, this defect is associated with impaired sonic hedgehog (Shh) secretion and intraluminal vesicle (ILV) formation in multivesicular bodies (MVBs). Furthermore, we show CHMP1A is important for release of an EV subtype that contains AXL, RAB18, and TMED10 (ART) and SHH. Our findings show CHMP1A loss impairs secretion of SHH on ART-EVs, providing molecular mechanistic insights into the role of ESCRT proteins and EVs in the brain.

Original language	English (US)
Pages (from-to)	973-986.e8
Journal	Cell reports
Volume	24
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2018.06.100
State	Published - Jul 24 2018

Funding

We thank patients and their families for their participation, Jen Partlow for collecting patient MRIs, Brenda Barry for coordinating skin fibroblast collection, Margaret Thompson for Chmp1a GT mouse line generation, Stan Hollenberg for CHMP1A antibody, Corey Harwell for mNG-SHH plasmid, Adrian Salic for SHH plasmid, and Chad Cowan and Kirin Musunuru for CRISPR plasmids. We thank Maria Ericsson, Louise Trakimas, and Elizabeth Benecchi for TEM sample preparation and imaging. We thank Bill Fowle for SEM sample preparation and imaging. This work was supported by NIH R01 NS088566 and the New York Stem Cell Foundation (M.K.L.); M.K.L. is a New York Stem Cell Foundation-Robertson investigator. C.A.W. was supported by NINDS R01 NS35129 and MEC F30 MH102909. C.A.W. and D.H. are Investigators of the Howard Hughes Medical Institute. R.G. was supported by the IdEx Université de Strasbourg via the Agence Nationale de la Recherche (ANR) as part of the program “investissements d'avenir” and the ATIP-Avenir program. T.K. and R.G. were supported by NIH U19AI109740 (to T.K. and R.G.) and NIH GM075252 (to T.K.). S.C. and F.D. were supported by ANR and the French Proteomic Infrastructure (ProFI) (ANR-10-INBS-08-03). M.E.C. was supported by a Howard Hughes Medical Institute Medical Student Fellowship and Nancy Lurie Marks Family Foundation Medical Student Fellowship. We thank patients and their families for their participation, Jen Partlow for collecting patient MRIs, Brenda Barry for coordinating skin fibroblast collection, Margaret Thompson for Chmp1a GT mouse line generation, Stan Hollenberg for CHMP1A antibody, Corey Harwell for mNG-SHH plasmid, Adrian Salic for SHH plasmid, and Chad Cowan and Kirin Musunuru for CRISPR plasmids. We thank Maria Ericsson, Louise Trakimas, and Elizabeth Benecchi for TEM sample preparation and imaging. We thank Bill Fowle for SEM sample preparation and imaging. This work was supported by NIH R01 NS088566 and the New York Stem Cell Foundation (M.K.L.); M.K.L. is a New York Stem Cell Foundation-Robertson investigator. C.A.W. was supported by NINDS R01 NS35129 and MEC F30 MH102909 . C.A.W. and D.H. are Investigators of the Howard Hughes Medical Institute. R.G. was supported by the IdEx Université de Strasbourg via the Agence Nationale de la Recherche (ANR) as part of the program “investissements d’avenir” and the ATIP-Avenir program. T.K. and R.G. were supported by NIH U19AI109740 (to T.K. and R.G.) and NIH GM075252 (to T.K.). S.C. and F.D. were supported by ANR and the French Proteomic Infrastructure (ProFI) ( ANR-10-INBS-08-03 ). M.E.C. was supported by a Howard Hughes Medical Institute Medical Student Fellowship and Nancy Lurie Marks Family Foundation Medical Student Fellowship. We thank patients and their families for their participation, Jen Partlow for collecting patient MRIs, Brenda Barry for coordinating skin fibroblast collection, Margaret Thompson for Chmp1a GT mouse line generation, Stan Hollenberg for CHMP1A antibody, Corey Harwell for mNG-SHH plasmid, Adrian Salic for SHH plasmid, and Chad Cowan and Kirin Musunuru for CRISPR plasmids. We thank Maria Ericsson, Louise Trakimas, and Elizabeth Benecchi for TEM sample preparation and imaging. We thank Bill Fowle for SEM sample preparation and imaging. This work was supported by NIH R01 NS088566 and the New York Stem Cell Foundation (M.K.L.); M.K.L. is a New York Stem Cell Foundation-Robertson investigator. C.A.W. was supported by NINDS R01 NS35129 and MEC F30 MH102909. C.A.W. and D.H. are Investigators of the Howard Hughes Medical Institute. R.G. was supported by the IdEx Universit? de Strasbourg via the Agence Nationale de la Recherche (ANR) as part of the program ?investissements d'avenir? and the ATIP-Avenir program. T.K. and R.G. were supported by NIH U19AI109740 (to T.K. and R.G.) and NIH GM075252 (to T.K.). S.C. and F.D. were supported by ANR and the French Proteomic Infrastructure (ProFI) (ANR-10-INBS-08-03). M.E.C. was supported by a Howard Hughes Medical Institute Medical Student Fellowship and Nancy Lurie Marks Family Foundation Medical Student Fellowship.

Keywords

CHMP1A
ESCRT
extracellular vesicles
microcephaly
multivesicular body
neurodevelopment
sonic hedgehog

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2018.06.100

Cite this

Coulter, M. E., Dorobantu, C. M., Lodewijk, G. A., Delalande, F., Cianferani, S., Ganesh, V. S., Smith, R. S., Lim, E. T., Xu, C. S., Pang, S., Wong, E. T., Lidov, H. G. W., Calicchio, M. L., Yang, E., Gonzalez, D. M., Schlaeger, T. M., Mochida, G. H., Hess, H., Lee, W. C. A., ... Walsh, C. A. (2018). The ESCRT-III Protein CHMP1A Mediates Secretion of Sonic Hedgehog on a Distinctive Subtype of Extracellular Vesicles. Cell reports, 24(4), 973-986.e8. https://doi.org/10.1016/j.celrep.2018.06.100

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title = "The ESCRT-III Protein CHMP1A Mediates Secretion of Sonic Hedgehog on a Distinctive Subtype of Extracellular Vesicles",

abstract = "Endosomal sorting complex required for transport (ESCRT) complex proteins regulate biogenesis and release of extracellular vesicles (EVs), which enable cell-to-cell communication in the nervous system essential for development and adult function. We recently showed human loss-of-function (LOF) mutations in ESCRT-III member CHMP1A cause autosomal recessive microcephaly with pontocerebellar hypoplasia, but its mechanism was unclear. Here, we show Chmp1a is required for progenitor proliferation in mouse cortex and cerebellum and progenitor maintenance in human cerebral organoids. In Chmp1a null mice, this defect is associated with impaired sonic hedgehog (Shh) secretion and intraluminal vesicle (ILV) formation in multivesicular bodies (MVBs). Furthermore, we show CHMP1A is important for release of an EV subtype that contains AXL, RAB18, and TMED10 (ART) and SHH. Our findings show CHMP1A loss impairs secretion of SHH on ART-EVs, providing molecular mechanistic insights into the role of ESCRT proteins and EVs in the brain.",

keywords = "CHMP1A, ESCRT, extracellular vesicles, microcephaly, multivesicular body, neurodevelopment, sonic hedgehog",

author = "Coulter, {Michael E.} and Dorobantu, {Cristina M.} and Lodewijk, {Gerrald A.} and Fran{\c c}ois Delalande and Sarah Cianferani and Ganesh, {Vijay S.} and Smith, {Richard S.} and Lim, {Elaine T.} and Xu, {C. Shan} and Song Pang and Wong, {Eric T.} and Lidov, {Hart G.W.} and Calicchio, {Monica L.} and Edward Yang and Gonzalez, {Dilenny M.} and Schlaeger, {Thorsten M.} and Mochida, {Ganeshwaran H.} and Harald Hess and Lee, {Wei Chung Allen} and Lehtinen, {Maria K.} and Tomas Kirchhausen and David Haussler and Jacobs, {Frank M.J.} and Raphael Gaudin and Walsh, {Christopher A.}",

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s)",

year = "2018",

month = jul,

day = "24",

doi = "10.1016/j.celrep.2018.06.100",

language = "English (US)",

volume = "24",

pages = "973--986.e8",

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Coulter, ME, Dorobantu, CM, Lodewijk, GA, Delalande, F, Cianferani, S, Ganesh, VS, Smith, RS, Lim, ET, Xu, CS, Pang, S, Wong, ET, Lidov, HGW, Calicchio, ML, Yang, E, Gonzalez, DM, Schlaeger, TM, Mochida, GH, Hess, H, Lee, WCA, Lehtinen, MK, Kirchhausen, T, Haussler, D, Jacobs, FMJ, Gaudin, R & Walsh, CA 2018, 'The ESCRT-III Protein CHMP1A Mediates Secretion of Sonic Hedgehog on a Distinctive Subtype of Extracellular Vesicles', Cell reports, vol. 24, no. 4, pp. 973-986.e8. https://doi.org/10.1016/j.celrep.2018.06.100

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T1 - The ESCRT-III Protein CHMP1A Mediates Secretion of Sonic Hedgehog on a Distinctive Subtype of Extracellular Vesicles

AU - Coulter, Michael E.

AU - Dorobantu, Cristina M.

AU - Lodewijk, Gerrald A.

AU - Delalande, François

AU - Cianferani, Sarah

AU - Ganesh, Vijay S.

AU - Smith, Richard S.

AU - Lim, Elaine T.

AU - Xu, C. Shan

AU - Pang, Song

AU - Wong, Eric T.

AU - Lidov, Hart G.W.

AU - Calicchio, Monica L.

AU - Yang, Edward

AU - Gonzalez, Dilenny M.

AU - Schlaeger, Thorsten M.

AU - Mochida, Ganeshwaran H.

AU - Hess, Harald

AU - Lee, Wei Chung Allen

AU - Lehtinen, Maria K.

AU - Kirchhausen, Tomas

AU - Haussler, David

AU - Jacobs, Frank M.J.

AU - Gaudin, Raphael

AU - Walsh, Christopher A.

PY - 2018/7/24

Y1 - 2018/7/24

N2 - Endosomal sorting complex required for transport (ESCRT) complex proteins regulate biogenesis and release of extracellular vesicles (EVs), which enable cell-to-cell communication in the nervous system essential for development and adult function. We recently showed human loss-of-function (LOF) mutations in ESCRT-III member CHMP1A cause autosomal recessive microcephaly with pontocerebellar hypoplasia, but its mechanism was unclear. Here, we show Chmp1a is required for progenitor proliferation in mouse cortex and cerebellum and progenitor maintenance in human cerebral organoids. In Chmp1a null mice, this defect is associated with impaired sonic hedgehog (Shh) secretion and intraluminal vesicle (ILV) formation in multivesicular bodies (MVBs). Furthermore, we show CHMP1A is important for release of an EV subtype that contains AXL, RAB18, and TMED10 (ART) and SHH. Our findings show CHMP1A loss impairs secretion of SHH on ART-EVs, providing molecular mechanistic insights into the role of ESCRT proteins and EVs in the brain.

AB - Endosomal sorting complex required for transport (ESCRT) complex proteins regulate biogenesis and release of extracellular vesicles (EVs), which enable cell-to-cell communication in the nervous system essential for development and adult function. We recently showed human loss-of-function (LOF) mutations in ESCRT-III member CHMP1A cause autosomal recessive microcephaly with pontocerebellar hypoplasia, but its mechanism was unclear. Here, we show Chmp1a is required for progenitor proliferation in mouse cortex and cerebellum and progenitor maintenance in human cerebral organoids. In Chmp1a null mice, this defect is associated with impaired sonic hedgehog (Shh) secretion and intraluminal vesicle (ILV) formation in multivesicular bodies (MVBs). Furthermore, we show CHMP1A is important for release of an EV subtype that contains AXL, RAB18, and TMED10 (ART) and SHH. Our findings show CHMP1A loss impairs secretion of SHH on ART-EVs, providing molecular mechanistic insights into the role of ESCRT proteins and EVs in the brain.

KW - CHMP1A

KW - ESCRT

KW - extracellular vesicles

KW - microcephaly

KW - multivesicular body

KW - neurodevelopment

KW - sonic hedgehog

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The ESCRT-III Protein CHMP1A Mediates Secretion of Sonic Hedgehog on a Distinctive Subtype of Extracellular Vesicles

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