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Dendrite tapering actuates a self-organizing signaling circuit for stochastic filopodia initiation in neurons [Cell Biology]
Proceedings of the National Academy of Sciences of the United States of America  (IF11.205),  Pub Date : 2021-10-26, DOI: 10.1073/pnas.2106921118
Gloria Mancinelli, Lucas Lamparter, Georgii Nosov, Tanumoy Saha, Anna Pawluchin, Rainer Kurre, Christiane Rasch, Mirsana Ebrahimkutty, Jürgen Klingauf, Milos Galic

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.