Rozés-Salvador Victoria, Wilson Carlos, Olmos Cristina, Gonzalez-Billault Christian, Conde Cecilia
Instituto de Investigación Médica Mercedes y Martín Ferreyra INIMEC-CONICET-UNC, Córdoba, Argentina.
Instituto de Ciencias Básicas, Universidad Nacional de Villa María (UNVM), Córdoba, Argentina.
Front Cell Dev Biol. 2020 Sep 3;8:550267. doi: 10.3389/fcell.2020.550267. eCollection 2020.
Neural development is a complex process that involves critical events, including cytoskeleton dynamics and selective trafficking of proteins to defined cellular destinations. In this regard, Smad Anchor for Receptor Activation (SARA) is an early endosome resident protein, where perform trafficking- associated functions. In addition, SARA is also involved in cell signaling, including the TGFβ-dependent pathway. Accordingly, SARA, and TGFβ signaling are required for proper axonal specification and migration of cortical neurons, unveiling a critical role for neuronal development. However, the cooperative action between the TGFβ pathway and SARA to this process has remained understudied. In this work, we show novel evidence suggesting a cross-talk between SARA and TGFβ pathway needed for proper polarization, axonal specification, growth and cortical migration of central neurons both and . Using microscopy tools and cultured hippocampal neurons, we show a local interaction between SARA and TβRI (TGFβ I receptor) at endosomes. In addition, SARA loss of function, induced by the expression of the dominant-negative SARA-F728A, over-activates the TGFβ pathway, most likely by preserving phosphorylated TβRI. Consequently, SARA-mediated activation of TGFβ pathway impacts on neuronal development, promoting axonal growth and cortical migration of neurons during brain development. Moreover, our data suggests that SARA basally prevents the activation of TβRI through the recruitment of the inhibitory complex PP1c/GADD34 in polarizing neurons. Together, these results propose that SARA is a negative regulator of the TGFβ pathway, being critical for a proper orchestration for neuronal development.
神经发育是一个复杂的过程，涉及关键事件，包括细胞骨架动力学以及蛋白质向特定细胞目的地的选择性运输。在这方面，受体激活的Smad锚定蛋白（SARA）是一种早期内体驻留蛋白，在其中发挥与运输相关的功能。此外，SARA还参与细胞信号传导，包括TGFβ依赖性途径。因此，SARA和TGFβ信号传导是皮质神经元正确轴突特化和迁移所必需的，揭示了其在神经元发育中的关键作用。然而，TGFβ途径与SARA在此过程中的协同作用仍未得到充分研究。在这项工作中，我们展示了新的证据，表明SARA与TGFβ途径之间存在相互作用，这对于中枢神经元在[此处原文缺失相关内容]的正确极化、轴突特化、生长和皮质迁移是必需的。使用显微镜工具和培养的海马神经元，我们展示了SARA与内体上的TβRI（TGFβ I型受体）之间的局部相互作用。此外，由显性负性SARA - F728A的表达诱导的SARA功能丧失，最有可能通过保留磷酸化的TβRI过度激活TGFβ途径。因此，SARA介导的TGFβ途径激活影响神经元发育，在脑发育过程中促进神经元的轴突生长和皮质迁移。此外，我们的数据表明，SARA在极化神经元中通过募集抑制复合物PP1c / GADD34从根本上阻止TβRI激活。总之，这些结果表明SARA是TGFβ途径的负调节因子，对于神经元发育的正确协调至关重要。
