Paillard Théo, Allam Ada, Doulazmi Mohamed, Hautefeuille Mathieu, Fouquet Coralie, Sarde Liza, Stoufflet Julie, Messaoudi Salima, Spassky Nathalie, Nédélec Stéphane, Dusart Isabelle, Trembleau Alain
Sorbonne Université, CNRS, INSERM, NeuroSU, F-75005 Paris, France.
Sorbonne Université, CNRS, INSERM, Institut de Biologie Paris Seine, IBPS, F-75005 Paris, France.
Sci Adv. 2025 Aug;11(31):eadx3846. doi: 10.1126/sciadv.adx3846. Epub 2025 Jul 30.
The saltatory migration of neurons is essential for brain formation. Whether mechanical stimuli regulate this process is unknown. Here, we show that the primary cilium acts as a mechanical sensor through GPR161. Using an ex vivo neuronal migration model and microfluidic assays, we demonstrate that fluid shear stress induces migration via the mechanoreceptor GPR161 at the primary cilium, with its mechanosensitive helix 8 being essential. We demonstrate that GPR161 activates a recently discovered cAMP/PKA signaling pathway leading to the phosphorylation of NDE1, a dynein complex regulator, and microtubule organization to regulate migration. These findings unveil a critical role of mechanosensation in neuronal migration, regulating the rhythmicity of migration, in concert with the externalization/internalization dynamics of the primary cilium.
神经元的跳跃式迁移对大脑形成至关重要。机械刺激是否调节这一过程尚不清楚。在这里，我们表明初级纤毛通过GPR161作为机械传感器。使用离体神经元迁移模型和微流控分析，我们证明流体剪切应力通过初级纤毛处的机械感受器GPR161诱导迁移，其机械敏感螺旋8至关重要。我们证明GPR161激活了最近发现的cAMP/PKA信号通路，导致动力蛋白复合体调节因子NDE1的磷酸化以及微管组织以调节迁移。这些发现揭示了机械感觉在神经元迁移中的关键作用，与初级纤毛的外化/内化动态协同调节迁移的节律性。
