Sorbonne Université, CNRS UMR8246, Inserm U1130, Institut de Biologie Paris Seine (IBPS), Neuroscience Paris Seine (NPS), Paris, France.
Laboratory of Molecular Regulation of Neurogenesis, GIGA-Stem Cells and GIGA-Neurosciences, University of Liège, CHU Sart Tilman, Liège, Belgium.
Elife. 2024 May 17;12:RP88782. doi: 10.7554/eLife.88782.
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 -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 mRNA target implicated in these migratory defects is microtubule-associated protein 1B (MAP1B). 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）是最常见的遗传性智力障碍形式，也是自闭症谱系障碍的第一个单基因病因。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，它允许神经元从其生发龛位迁移到最终的整合部位。FMRP 在神经元迁移中的精确作用在很大程度上仍未得到探索。我们利用 -null 小鼠出生后额迁移流（RMS）神经元的实时成像，观察到 FMRP 的缺失导致神经元迁移延迟和轨迹改变，与中心体运动缺陷有关。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，在这些迁移缺陷中涉及的主要 mRNA 靶标是微管相关蛋白 1B（MAP1B）。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 的缺失诱导了迁移神经元核周围微管笼的缺陷来阐明起作用的分子机制，MAP1B 的敲低可挽救这些缺陷。我们的研究结果揭示了 FMRP 与 MAP1B 共同协作在神经发育中的新作用，共同通过影响微管细胞骨架来协调神经元迁移。
