Format

Send to

Choose Destination
Cell Rep. 2018 Jul 24;24(4):973-986.e8. 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.

Author information

1
Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA; Program in Neuroscience and Harvard/MIT MD-PHD Program, Harvard Medical School, Boston, MA 02115, USA.
2
Inserm U1110, Université de Strasbourg, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
3
University of Amsterdam, Swammerdam Institute for Life Sciences, 1098 XH Amsterdam, the Netherlands.
4
Laboratoire de Spectrométrie de Masse Bio-Organique, IPHC, UMR 7178, CNRS-Université de Strasbourg, ECPM, 67087 Strasbourg, France.
5
Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
6
Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
7
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
8
Brain Tumor Center and Neuro-Oncology Unit, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
9
Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
10
Department of Radiology, Boston Children's Hospital, Boston, MA 02115, USA.
11
Division of Hematology and Oncology, Boston Children's Hospital, Boston, MA 02115, USA.
12
Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
13
F.M. Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
14
Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
15
Center for Biomolecular Science and Engineering, University of California and Howard Hughes Medical Institute, Santa Cruz, CA 95064, USA.
16
University of Amsterdam, Swammerdam Institute for Life Sciences, 1098 XH Amsterdam, the Netherlands. Electronic address: f.m.j.jacobs@uva.nl.
17
Inserm U1110, Université de Strasbourg, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France; Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: rgaudin@unistra.fr.
18
Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: christopher.walsh@childrens.harvard.edu.

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

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center