Neural Circuit Development and Regeneration Research Group, Department of Biology, KU Leuven, Naamsestraat 61, box 2464, 3000, Leuven, Belgium.
Department of Neuroscience and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), University of Montréal, Montréal, QC, Canada.
Mol Neurobiol. 2019 May;56(5):3175-3192. doi: 10.1007/s12035-018-1292-5. Epub 2018 Aug 13.
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 that-as during development-RGC 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.
神经损伤和神经退行性疾病通常会导致永久性的功能缺陷，因此寻找新的促修复分子和机制成为研究的重点。目前，神经修复研究主要集中在促进轴突再生，而树突的再生特性则在很大程度上尚未得到研究。此外，尽管发育研究表明轴突发生和树突发生之间存在严格的时间分离，因此暗示了轴突和树突生长之间存在潜在的相互依赖性，但在再生过程中轴突-树突相互作用的可能性仍未得到探索。为了揭示成功进行轴突再生的脊椎动物神经元固有的树突反应，本研究使用了雄性和雌性成年斑马鱼，对其视神经进行挤压（ONC）。这是一项纵向研究，在视神经挤压后，同时评估视网膜神经节细胞（RGC）树突重塑和轴突再生情况。结果表明，在中枢神经系统（CNS）修复过程中，RGC 轴突发生先于树突发生，就像在发育过程中一样。此外，在轴突再生开始之前，树突主要收缩，只有在与 RGC 靶标接触开始后才被触发进行再生，这表明神经元损伤后轴突和树突之间存在拮抗相互作用。引人注目的是，视神经挤压后视网膜机械靶蛋白（mTOR）和广谱基质金属蛋白酶（MMP）抑制连续抑制了 RGC 突触-树突退化和轴突再生，从而激活了拮抗相互作用，其中成熟的树突抑制了轴突再生。总之，这项工作将树突收缩作为成年脊椎动物神经元有效轴突再生的前提，并表明损伤后树突反应的分子/机制分析可能成为神经修复的强大靶点发现平台。
