Messaoudi Salima, Allam Ada, Stoufflet Julie, Paillard Théo, Fouquet Coralie, Doulazmi Mohamed, Le Ven Anaïs, Trembleau Alain, Caillé Isabelle
bioRxiv. 2023 Dec 28:2023.03.06.530447. doi: 10.1101/2023.03.06.530447.
The Fragile X Syndrome (FXS) represents the most prevalent form of inherited intellectual disability and is the first monogenic cause of Autism Spectrum Disorder. FXS results from the absence of the RNA-binding protein FMRP (Fragile X Messenger Ribonucleoprotein). Neuronal migration is an essential step of brain development allowing displacement of neurons from their germinal niches to their final integration site. The precise role of FMRP in neuronal migration remains largely unexplored. Using live imaging of postnatal Rostral Migratory Stream (RMS) neurons in Fmr1-null mice, we observed that the absence of FMRP leads to delayed neuronal migration and altered trajectory, associated with defects of centrosomal movement. RNA-interference-induced knockdown of shows that these migratory defects are cell-autonomous. Notably, the primary FMRP mRNA target implicated in these migratory defects is MAP1B (Microtubule-Associated Protein 1B). Knocking-down MAP1B expression effectively rescued most of the observed migratory defects. Finally, we elucidate the molecular mechanisms at play by demonstrating that the absence of FMRP induces defects in the cage of microtubules surrounding the nucleus of migrating neurons, which is rescued by MAP1B knockdown. Our findings reveal a novel neurodevelopmental role for FMRP in collaboration with MAP1B, jointly orchestrating neuronal migration by influencing the microtubular cytoskeleton.
脆性X综合征（FXS）是遗传性智力障碍最常见的形式，也是自闭症谱系障碍的首个单基因病因。FXS是由于RNA结合蛋白FMRP（脆性X信使核糖核蛋白）缺失所致。神经元迁移是大脑发育的一个重要步骤，它使神经元从其生发龛移位至最终整合位点。FMRP在神经元迁移中的具体作用在很大程度上仍未得到探索。通过对Fmr1基因敲除小鼠出生后吻侧迁移流（RMS）神经元进行实时成像，我们观察到FMRP的缺失导致神经元迁移延迟和轨迹改变，并伴有中心体运动缺陷。RNA干扰诱导的 敲低表明这些迁移缺陷是细胞自主性的。值得注意的是，与这些迁移缺陷相关的主要FMRP mRNA靶点是MAP1B（微管相关蛋白1B）。敲低MAP1B表达可有效挽救大部分观察到的迁移缺陷。最后，我们通过证明FMRP的缺失会导致围绕迁移神经元细胞核的微管笼出现缺陷，而敲低MAP1B可挽救该缺陷，从而阐明了其中的分子机制。我们的研究结果揭示了FMRP与MAP1B协同作用的一种新的神经发育作用，即通过影响微管细胞骨架共同协调神经元迁移。
