Neuron connectivity depends on growth cones that navigate axons through the developing brain. Growth cones protrude and retract actin-rich structures to sense guidance cues. These cues control local actin dynamics and steer growth cones towards attractants and away from repellents, thereby directing axon outgrowth. Hence, actin binding proteins (ABPs) moved into the focus as critical regulators of neuron connectivity. We found cyclase-associated protein 1 (CAP1), an ABP with unknown brain function, abundant in growth cones. Super-resolution microscopy and live cell imaging combined with pharmacological approaches on hippocampal neurons from gene-targeted mice revealed a crucial role for CAP1 in actin dynamics that is critical for growth cone morphology and function. Growth cone defects in CAP1 knockout (KO) neurons compromised neuron differentiation and was associated with impaired neuron connectivity in CAP1-KO brains. Mechanistically, by rescue experiments in double KO neurons lacking CAP1 and the key actin regulator cofilin1, we demonstrated that CAP1 was essential for cofilin1 function in growth cone actin dynamics and morphology and vice versa. Together, we identified CAP1 as a novel actin regulator in growth cones that was relevant for neuron connectivity, and we demonstrated functional interdependence of CAP1 and cofilin1 in neuronal actin dynamics and growth cone function.

神经元连接依赖于通过发育中的大脑导航轴突的生长锥。生长锥突出和缩回富含肌动蛋白的结构以感知引导线索。这些线索控制局部肌动蛋白动力学并将生长锥导向引诱剂并远离驱虫剂，从而指导轴突生长。因此，肌动蛋白结合蛋白 (ABP) 作为神经元连接的关键调节因子成为焦点。我们发现环化酶相关蛋白 1 (CAP1)，一种具有未知脑功能的 ABP，在生长锥中含量丰富。超分辨率显微镜和活细胞成像与基因靶向小鼠海马神经元的药理学方法相结合，揭示了 CAP1 在肌动蛋白动力学中的关键作用，这对生长锥的形态和功能至关重要。CAP1 敲除 (KO) 神经元中的生长锥缺陷损害了神经元分化，并与 CAP1-KO 大脑中的神经元连接受损有关。从机制上讲，通过在缺乏 CAP1 和关键肌动蛋白调节剂 cofilin1 的双 KO 神经元中进行救援实验，我们证明 CAP1 在生长锥肌动蛋白动力学和形态学中对 cofilin1 功能至关重要。反之亦然。总之，我们将 CAP1 确定为生长锥中与神经元连接相关的新型肌动蛋白调节剂，并且我们证明了 CAP1 和 cofilin1 在神经元肌动蛋白动力学和生长锥功能中的功能相互依赖性。