Axon guidance molecules are critical for neuronal pathfinding because they regulate directionality and growth pace during nervous system development. However, the molecular mechanisms coordinating proper axonal extension and turning are poorly understood. Here, Metastasis Suppressor 1 (Mtss1), a membrane protrusion protein, ensured axonal extension while sensitizing axons to the Semaphorin 3E (Sema3E)-Plexin-D1 repulsive cue. Sema3E-Plexin-D1 signaling enhanced Mtss1 expression in projecting striatonigral neurons. Mtss1 localized to the neurite axonal side and regulated neurite outgrowth in cultured neurons. Mtss1 also aided Plexin-D1 trafficking to the growth cone, where it signaled a repulsive cue to Sema3E. Mtss1 ablation reduced neurite extension and growth cone collapse in cultured neurons. Mtss1-knockout mice exhibited fewer striatonigral projections and irregular axonal routes and these defects were recapitulated in Plxnd1- or Sema3e-knockout mice. These findings demonstrate that repulsive axon guidance activates an exquisite autoregulatory program coordinating both axonal extension and steering during neuronal pathfinding.

中文翻译：

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排斥性 Sema3E-Plexin-D1 信号通过激活自动调节因子 Mtss1 来协调轴突延伸和转向

轴突引导分子对于神经元寻路至关重要，因为它们在神经系统发育过程中调节方向性和生长速度。然而，人们对协调轴突适当延伸和转向的分子机制知之甚少。在此，转移抑制蛋白 1 (Mtss1)（一种膜突出蛋白）确保轴突延伸，同时使轴突对信号蛋白 3E (Sema3E)-Plexin-D1 排斥信号敏感。 Sema3E-Plexin-D1 信号传导增强了投射纹状体黑质神经元中 Mtss1 的表达。 Mtss1 定位于神经突轴突侧并调节培养神经元中的神经突生长。 Mtss1 还帮助 Plexin-D1 运输到生长锥，在那里它向 Sema3E 发出排斥信号。 Mtss1 消融减少了培养神经元中的神经突延伸和生长锥塌陷。Mtss1敲除小鼠表现出较少的纹状体黑质投射和不规则的轴突路线，这些缺陷在Plxnd1或Sema3e敲除小鼠中重现。这些发现表明，排斥性轴突引导激活了一种精致的自动调节程序，在神经元寻路过程中协调轴突延伸和转向。