An Antagonistic Axon-Dendrite Interplay Enables Efficient Neuronal Repair in the Adult Zebrafish Central Nervous System
An Antagonistic Axon-Dendrite Interplay Enables Efficient Neuronal Repair in the Adult Zebrafish Central Nervous System
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DOI：
10.1007/s12035-018-1292-5
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发表时间：
2019-05-01
影响因子：
5.1
通讯作者：
Moons, Lieve
中科院分区：
文献类型：
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作者：
Beckers, An;Van Dyck, Annelies;Moons, Lieve
神经损伤和神经退行性疾病通常会导致永久性功能缺陷，这使得识别新的促再生分子和机制成为主要研究课题。如今，神经再生研究主要集中在促进轴突再生，而树突的再生特性在很大程度上未被研究。此外，而发育研究表明，严格的时间分离的轴突和树突，从而表明轴突和树突的生长的潜在的相互依赖性，在再生过程中可能的轴突-树突的相互作用仍然是未知的。要解开固有的树突状反应的脊椎动物神经元经历成功的轴突再生，再生能力的成年斑马鱼的任何性别，视神经挤压（ONC），使用。一项纵向研究对ONC后视网膜神经节细胞（RGC）树突重塑和轴突再生进行了并排评估，结果显示，在发育过程中，RGC轴突发生先于中枢神经系统（CNS）修复过程中的树突发生。此外，树突主要在轴突再生开始之前收缩，并且仅在RGC靶接触开始后才被触发再生，这完全表明神经元损伤后轴突和树突之间的相互作用。引人注目的是，ONC后视网膜雷帕霉素机制靶点（mTOR）和广谱基质金属蛋白酶（MMP）抑制连续抑制RGC突触-树突退化和轴突再生，从而增强了成熟树突抑制轴突再生的拮抗相互作用。总而言之，这项工作启动树突收缩作为成年脊椎动物神经元有效轴突再生的先决条件，并表明损伤后树突反应的分子/机制分析可能是神经修复的一个强大的目标发现平台。
Neural insults and neurodegenerative diseases typically result in permanent functional deficits, making the identification of novel pro-regenerative molecules and mechanisms a primary research topic. Nowadays, neuroregenerative research largely focuses on improving axonal regrowth, leaving the regenerative properties of dendrites largely unstudied. Moreover, whereas developmental studies indicate a strict temporal separation of axogenesis and dendritogenesis and thus suggest a potential interdependency of axonal and dendritic outgrowth, a possible axon-dendrite interaction during regeneration remains unexplored. To unravel the inherent dendritic response of vertebrate neurons undergoing successful axonal regeneration, regeneration-competent adult zebrafish of either sex, subjected to optic nerve crush (ONC), were used. A longitudinal study in which retinal ganglion cell (RGC) dendritic remodeling and axonal regrowth were assessed side-by-side after ONC, revealed thatas during developmentRGC axogenesis precedes dendritogenesis during central nervous system (CNS) repair. Moreover, dendrites majorly shrank before the start of axonal regrowth and were only triggered to regrow upon RGC target contact initiation, altogether suggestive for a counteractive interplay between axons and dendrites after neuronal injury. Strikingly, both retinal mechanistic target of rapamycin (mTOR) and broad-spectrum matrix metalloproteinase (MMP) inhibition after ONC consecutively inhibited RGC synapto-dendritic deterioration and axonal regrowth, thus invigorating an antagonistic interplay wherein mature dendrites restrain axonal regrowth. Altogether, this work launches dendritic shrinkage as a prerequisite for efficient axonal regrowth of adult vertebrate neurons, and indicates that molecular/mechanistic analysis of dendritic responses after damage might represent a powerful target-discovery platform for neural repair.