Dolique Tiphaine, Baudet Sarah, Charron Frederic, Ferent Julien
Montreal Clinical Research Institute (IRCM), 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada.
Department of Anatomy and Cell Biology, Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada.
iScience. 2025 Mar 26;28(5):112293. doi: 10.1016/j.isci.2025.112293. eCollection 2025 May 16.
Sonic hedgehog (Shh) is an axon guidance molecule that can act as either a chemorepellent or a chemoattractant, depending on the neuron type and their developmental stage. In the developing spinal cord, Shh initially attracts commissural axons to the floor plate and later repels them after they cross the midline. In the developing visual system, Shh repels ipsilateral retinal ganglion cell (iRGC) axons at the optic chiasm. Although Shh requires the endocytic adaptor Numb for attraction of spinal commissural axons, the molecular mechanisms underlying Shh dual function in attraction and repulsion are still unclear. In this study, we show that Numb is essential for two Shh-mediated repulsion processes: iRGC axon repulsion at the optic chiasm and antero-posterior commissural axon repulsion in the spinal cord. Therefore, Numb is required for Shh-mediated attraction and repulsion. These results position Numb as a central player in the non-canonical Shh signaling pathway mediating axon repulsion.
音猬因子（Shh）是一种轴突导向分子，根据神经元类型及其发育阶段，它既可以作为化学排斥剂，也可以作为化学吸引剂。在发育中的脊髓中，Shh最初将连合轴突吸引至底板，而在它们穿过中线后，Shh会排斥这些轴突。在发育中的视觉系统中，Shh在视交叉处排斥同侧视网膜神经节细胞（iRGC）轴突。尽管Shh在吸引脊髓连合轴突时需要内吞衔接蛋白Numb，但其在吸引和排斥中发挥双重功能的分子机制仍不清楚。在本研究中，我们表明Numb对于Shh介导的两个排斥过程至关重要：视交叉处的iRGC轴突排斥以及脊髓中前后连合轴突排斥。因此，Numb是Shh介导的吸引和排斥所必需的。这些结果表明Numb是介导轴突排斥的非经典Shh信号通路中的核心因子。
