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

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) mutat...

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Autores principales: Coulter, Michael E., Dorobantu, Cristina M., Lodewijk, Gerrald A., Delalande, François, Cianferani, Sarah, Ganesh, Vijay S., Smith, Richard S., Lim, Elaine T., Xu, C. Shan, Pang, Song, Wong, Eric T., Lidov, Hart G.W., Calicchio, Monica L., Yang, Edward, Gonzalez, Dilenny M., Schlaeger, Thorsten M., Mochida, Ganeshwaran H., Hess, Harald, Allen Lee, Wei-Chung, Lehtinen, Maria K., Kirchhausen, Tomas, Haussler, David, Jacobs, Frank M.J., Gaudin, Raphael, Walsh, Christopher A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178983/
https://www.ncbi.nlm.nih.gov/pubmed/30044992
http://dx.doi.org/10.1016/j.celrep.2018.06.100
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author Coulter, Michael E.
Dorobantu, Cristina M.
Lodewijk, Gerrald A.
Delalande, François
Cianferani, Sarah
Ganesh, Vijay S.
Smith, Richard S.
Lim, Elaine T.
Xu, C. Shan
Pang, Song
Wong, Eric T.
Lidov, Hart G.W.
Calicchio, Monica L.
Yang, Edward
Gonzalez, Dilenny M.
Schlaeger, Thorsten M.
Mochida, Ganeshwaran H.
Hess, Harald
Allen Lee, Wei-Chung
Lehtinen, Maria K.
Kirchhausen, Tomas
Haussler, David
Jacobs, Frank M.J.
Gaudin, Raphael
Walsh, Christopher A.
author_facet Coulter, Michael E.
Dorobantu, Cristina M.
Lodewijk, Gerrald A.
Delalande, François
Cianferani, Sarah
Ganesh, Vijay S.
Smith, Richard S.
Lim, Elaine T.
Xu, C. Shan
Pang, Song
Wong, Eric T.
Lidov, Hart G.W.
Calicchio, Monica L.
Yang, Edward
Gonzalez, Dilenny M.
Schlaeger, Thorsten M.
Mochida, Ganeshwaran H.
Hess, Harald
Allen Lee, Wei-Chung
Lehtinen, Maria K.
Kirchhausen, Tomas
Haussler, David
Jacobs, Frank M.J.
Gaudin, Raphael
Walsh, Christopher A.
author_sort Coulter, Michael E.
collection PubMed
description 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.
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spelling pubmed-61789832018-10-10 The ESCRT-III Protein CHMP1A Mediates Secretion of Sonic Hedgehog on a Distinctive Subtype of Extracellular Vesicles Coulter, Michael E. Dorobantu, Cristina M. Lodewijk, Gerrald A. Delalande, François Cianferani, Sarah Ganesh, Vijay S. Smith, Richard S. Lim, Elaine T. Xu, C. Shan Pang, Song Wong, Eric T. Lidov, Hart G.W. Calicchio, Monica L. Yang, Edward Gonzalez, Dilenny M. Schlaeger, Thorsten M. Mochida, Ganeshwaran H. Hess, Harald Allen Lee, Wei-Chung Lehtinen, Maria K. Kirchhausen, Tomas Haussler, David Jacobs, Frank M.J. Gaudin, Raphael Walsh, Christopher A. Cell Rep Article 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. 2018-07-24 /pmc/articles/PMC6178983/ /pubmed/30044992 http://dx.doi.org/10.1016/j.celrep.2018.06.100 Text en This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Coulter, Michael E.
Dorobantu, Cristina M.
Lodewijk, Gerrald A.
Delalande, François
Cianferani, Sarah
Ganesh, Vijay S.
Smith, Richard S.
Lim, Elaine T.
Xu, C. Shan
Pang, Song
Wong, Eric T.
Lidov, Hart G.W.
Calicchio, Monica L.
Yang, Edward
Gonzalez, Dilenny M.
Schlaeger, Thorsten M.
Mochida, Ganeshwaran H.
Hess, Harald
Allen Lee, Wei-Chung
Lehtinen, Maria K.
Kirchhausen, Tomas
Haussler, David
Jacobs, Frank M.J.
Gaudin, Raphael
Walsh, Christopher A.
The ESCRT-III Protein CHMP1A Mediates Secretion of Sonic Hedgehog on a Distinctive Subtype of Extracellular Vesicles
title The ESCRT-III Protein CHMP1A Mediates Secretion of Sonic Hedgehog on a Distinctive Subtype of Extracellular Vesicles
title_full The ESCRT-III Protein CHMP1A Mediates Secretion of Sonic Hedgehog on a Distinctive Subtype of Extracellular Vesicles
title_fullStr The ESCRT-III Protein CHMP1A Mediates Secretion of Sonic Hedgehog on a Distinctive Subtype of Extracellular Vesicles
title_full_unstemmed The ESCRT-III Protein CHMP1A Mediates Secretion of Sonic Hedgehog on a Distinctive Subtype of Extracellular Vesicles
title_short The ESCRT-III Protein CHMP1A Mediates Secretion of Sonic Hedgehog on a Distinctive Subtype of Extracellular Vesicles
title_sort escrt-iii protein chmp1a mediates secretion of sonic hedgehog on a distinctive subtype of extracellular vesicles
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178983/
https://www.ncbi.nlm.nih.gov/pubmed/30044992
http://dx.doi.org/10.1016/j.celrep.2018.06.100
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