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.
Inserm U1110, Université de Strasbourg, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
Cell Rep. 2018 Jul 24;24(4):973-986.e8. doi: 10.1016/j.celrep.2018.06.100.
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.
内体分选复合物需要运输（ESCRT）复合物蛋白调节细胞外囊泡（EVs）的生物发生和释放，这对于神经系统中的细胞间通讯至关重要，对于发育和成年功能至关重要。我们最近发现，人类 ESCRT-III 成员 CHMP1A 的功能丧失（LOF）突变导致常染色体隐性小头畸形伴桥小脑发育不良，但其机制尚不清楚。在这里，我们表明 Chmp1a 对于小鼠皮层和小脑的祖细胞增殖以及人类大脑类器官的祖细胞维持是必需的。在 Chmp1a 缺失的小鼠中，这一缺陷与 sonic hedgehog (Shh) 分泌和多泡体（MVBs）中腔内小泡（ILV）形成受损有关。此外，我们表明 CHMP1A 对于包含 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 的缺失会损害 ART-EVs 上 SHH 的分泌，为 ESCRT 蛋白和 EVs 在大脑中的作用提供了分子机制见解。
