How signaling units spontaneously arise from a noisy cellular background is not well understood. Here, we show that stochastic membrane deformations can nucleate exploratory dendritic filopodia, dynamic actin-rich structures used by neurons to sample its surroundings for compatible transcellular contacts. A theoretical analysis demonstrates that corecruitment of positive and negative curvature-sensitive proteins to deformed membranes minimizes the free energy of the system, allowing the formation of long-lived curved membrane sections from stochastic membrane fluctuations. Quantitative experiments show that once recruited, curvature-sensitive proteins form a signaling circuit composed of interlinked positive and negative actin-regulatory feedback loops. As the positive but not the negative feedback loop can sense the dendrite diameter, this self-organizing circuit determines filopodia initiation frequency along tapering dendrites. Together, our findings identify a receptor-independent signaling circuit that employs random membrane deformations to simultaneously elicit and limit formation of exploratory filopodia to distal dendritic sites of developing neurons.

信号单元如何从嘈杂的细胞背景中自发产生尚不清楚。在这里，我们表明随机膜变形可以使探索性树突丝状伪足成核，这是神经元用来对其周围环境进行采样以进行兼容的跨细胞接触的动态富含肌动蛋白的结构。理论分析表明，正负曲率敏感蛋白对变形膜的共同吸收使系统的自由能最小化，从而允许从随机膜波动中形成长寿命的弯曲膜部分。定量实验表明，一旦被招募，曲率敏感蛋白会形成一个由相互连接的正负肌动蛋白调节反馈回路组成的信号回路。由于正反馈回路而不是负反馈回路可以感知枝晶直径，这种自组织电路决定了沿着逐渐变细的树突的丝状伪足起始频率。总之，我们的研究结果确定了一个独立于受体的信号回路，该回路采用随机膜变形来同时引发和限制探索性丝状伪足形成到发育中神经元的远端树突状部位。