Feedback-Driven Assembly of the Axon Initial Segment

Amélie Fréal, Dipti Rai, Roderick P Tas, Xingxiu Pan, Eugene A Katrukha, Dieudonnée van de Willige, Riccardo Stucchi, Amol Aher, Chao Yang, A F Maarten Altelaar, Karin Vocking, Jan Andries Post, Martin Harterink, Lukas C Kapitein, Anna Akhmanova, Casper C Hoogenraad

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The axon initial segment (AIS) is a unique neuronal compartment that plays a crucial role in the generation of action potential and neuronal polarity. The assembly of the AIS requires membrane, scaffolding, and cytoskeletal proteins, including Ankyrin-G and TRIM46. How these components cooperate in AIS formation is currently poorly understood. Here, we show that Ankyrin-G acts as a scaffold interacting with End-Binding (EB) proteins and membrane proteins such as Neurofascin-186 to recruit TRIM46-positive microtubules to the plasma membrane. Using in vitro reconstitution and cellular assays, we demonstrate that TRIM46 forms parallel microtubule bundles and stabilizes them by acting as a rescue factor. TRIM46-labeled microtubules drive retrograde transport of Neurofascin-186 to the proximal axon, where Ankyrin-G prevents its endocytosis, resulting in stable accumulation of Neurofascin-186 at the AIS. Neurofascin-186 enrichment in turn reinforces membrane anchoring of Ankyrin-G and subsequent recruitment of TRIM46-decorated microtubules. Our study reveals feedback-based mechanisms driving AIS assembly.

Original languageEnglish
Pages (from-to)305-321.e8
Issue number2
Publication statusPublished - 2019


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