biostudies-literatureKim NNational Research Foundation of KoreaNational Research FoundationKorea Brain Research Institutee96891https://www.ebi.ac.uk/biostudies/studies/S-EPMC11001299biostudies-literatureUnknown13Axon 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. <i>Mtss1</i>-knockout mice exhibited fewer striatonigral projections and irregular axonal routes, and these defects were recapitulated in <i>Plxnd1</i>- or <i>Sema3e</i>-knockout mice. These findings demonstrate that repulsive axon guidance activates an exquisite autoregulatory program coordinating both axonal extension and steering during neuronal pathfinding.eLifeRepulsive Sema3E-Plexin-D1 signaling coordinates both axonal extension and steering via activating an autoregulatory factor, Mtss1.PMC11001299NRF-2022M3E5E8017701KBRI 23-BR-01-02NRF-2014R1A1A2058234NRF-2020M3E5D9079766Young Researcher Program 2020R1C1C1010509Jun MHJeong JYLi YKwon HSOh WJYu RSong ALim HHKim MJKim JWKim NLee JHfalseRepulsive Sema3E-Plexin-D1 signaling coordinates both axonal extension and steering via activating an autoregulatory factor, Mtss1.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. <i>Mtss1</i>-knockout mice exhibited fewer striatonigral projections and irregular axonal routes, and these defects were recapitulated in <i>Plxnd1</i>- or <i>Sema3e</i>-knockout mice. These findings demonstrate that repulsive axon guidance activates an exquisite autoregulatory program coordinating both axonal extension and steering during neuronal pathfinding.2024-01-01T00:00:00Z2024 Mar2026-06-01T19:56:40.226Z2025-05-29T19:24:42.3ZS-EPMC110012993852653510.7554/eLife.96891