Dopey-dependent regulation of extracellular vesicles maintains neuronal morphology.

IF 8.1 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Current Biology Pub Date : 2024-11-04 Epub Date: 2024-10-07 DOI:10.1016/j.cub.2024.09.018
Seungmee Park, Nathaniel Noblett, Lauren Pitts, Antonio Colavita, Ann M Wehman, Yishi Jin, Andrew D Chisholm
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Abstract

Mature neurons maintain their distinctive morphology for extended periods in adult life. Compared to developmental neurite outgrowth, axon guidance, and target selection, relatively little is known of mechanisms that maintain the morphology of mature neurons. Loss of function in C. elegans dip-2, a member of the conserved lipid metabolic regulator Dip2 family, results in progressive overgrowth of neurites in adults. We find that dip-2 mutants display specific genetic interactions with sax-2, the C. elegans ortholog of Drosophila Furry and mammalian FRY. Combined loss of dip-2 and sax-2 results in failure to maintain neuronal morphology and elevated release of neuronal extracellular vesicles (EVs). By screening for suppressors of dip-2(0) sax-2(0) double mutant defects, we identified gain-of-function (gf) mutations in the conserved Dopey family protein PAD-1 and its associated phospholipid flippase TAT-5/ATP9A that restore normal neuronal morphology and normal levels of EV release to dip-2(0) sax-2(0) double mutants. Neuron-specific knockdown suggests that PAD-1(gf) can act cell autonomously in neurons. PAD-1(gf) displays increased association with the plasma membrane in oocytes and inhibits EV release in multiple cell types. Our findings uncover a novel functional network of DIP-2, SAX-2, PAD-1, and TAT-5 that maintains neuronal morphology and modulates EV release.

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多派依赖性细胞外囊泡调节维持神经元形态
成熟神经元在成年后会长期保持其独特的形态。与神经元的发育、轴突导向和目标选择相比,人们对维持成熟神经元形态的机制知之甚少。elegans dip-2是保守的脂质代谢调节因子Dip2家族的成员,其功能缺失会导致神经元在成年后逐渐过度生长。我们发现,dip-2 突变体与 sax-2(果蝇 Furry 和哺乳动物 FRY 的线虫直向同源物)之间存在特定的遗传相互作用。dip-2和sax-2的联合缺失会导致神经元形态无法维持以及神经元胞外囊泡(EVs)的释放增加。通过筛选dip-2(0) sax-2(0)双突变体缺陷的抑制因子,我们发现了保守的Dopey家族蛋白PAD-1及其相关磷脂翻转酶TAT-5/ATP9A的功能增益(gf)突变,这些突变能使dip-2(0) sax-2(0)双突变体恢复正常的神经元形态和正常水平的EV释放。神经元特异性敲除表明,PAD-1(gf)可以在神经元中自主发挥作用。在卵母细胞中,PAD-1(gf)与质膜的关联性增强,并抑制多种细胞类型中的EV释放。我们的发现揭示了一个由 DIP-2、SAX-2、PAD-1 和 TAT-5 组成的新型功能网络,它能维持神经元形态并调节 EV 释放。
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来源期刊
Current Biology
Current Biology 生物-生化与分子生物学
CiteScore
11.80
自引率
2.20%
发文量
869
审稿时长
46 days
期刊介绍: Current Biology is a comprehensive journal that showcases original research in various disciplines of biology. It provides a platform for scientists to disseminate their groundbreaking findings and promotes interdisciplinary communication. The journal publishes articles of general interest, encompassing diverse fields of biology. Moreover, it offers accessible editorial pieces that are specifically designed to enlighten non-specialist readers.
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