The ESCRT-III Protein CHMP1A Mediates Secretion of Sonic Hedgehog on a Distinctive Subtype of Extracellular Vesicles.
The ESCRT-III Protein CHMP1A Mediates Secretion of Sonic Hedgehog on a Distinctive Subtype of Extracellular Vesicles.
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DOI：
10.1016/j.celrep.2018.06.100
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发表时间：
2018-07-24
期刊：
影响因子：
8.8
通讯作者：
Walsh CA
中科院分区：
文献类型：
--
作者：
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 WA;Lehtinen MK;Kirchhausen T;Haussler D;Jacobs FMJ;Gaudin R;Walsh CA
内体转运所需分选复合物（ESCRT）复杂蛋白调节细胞外囊泡（ev）的生物发生和释放，细胞外囊泡在神经系统中实现细胞间的通信，对发育和成人功能至关重要。我们最近发现ESCRT-III成员CHMP1A的人类功能缺失（LOF）突变可导致常染色体隐性小头畸形伴桥小脑发育不全，但其机制尚不清楚。在这里，我们发现Chmp1a是小鼠皮层和小脑祖细胞增殖和人类大脑类器官祖细胞维持所必需的。在Chmp1a缺失小鼠中，这种缺陷与多泡体（MVBs）中sonic hedgehog （Shh）分泌和腔内小泡（ILV）形成受损有关。此外，我们发现CHMP1A对于含有AXL、RAB18和TMED10 （ART）和SHH的EV亚型的释放很重要。我们的研究结果表明，CHMP1A缺失会损害art - ev上SHH的分泌，这为ESCRT蛋白和ev在大脑中的作用提供了分子机制的见解。细胞外囊泡（EVs）对发育中的大脑细胞间的通讯至关重要。Coulter等人发现，人类小头畸形基因CHMP1A通过调节生长因子SHH的水疱分泌，是神经祖细胞增殖所必需的。CHMP1A特异性地损害一种独特的EV亚型ART-EV上的SHH分泌。
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. Extracellular vesicles (EVs) are essential for cell-to-cell communication in developing brain. Coulter et al. show that the human microcephaly gene CHMP1A is required for neuroprogenitor proliferation through regulation of vesicular secretion of the growth factor sonic hedgehog (SHH). CHMP1A specifically impairs SHH secretion on a distinctive EV subtype, ART-EV.
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