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

Research output: Contribution to journal/periodicalArticleScientificpeer-review

49 Downloads (Pure)

Abstract

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
JournalNeuron
Volume104
Issue number2
DOIs
Publication statusPublished - 2019

Fingerprint Dive into the research topics of 'Feedback-Driven Assembly of the Axon Initial Segment'. Together they form a unique fingerprint.

  • Cite this

    Fréal, A., Rai, D., Tas, R. P., Pan, X., Katrukha, E. A., van de Willige, D., Stucchi, R., Aher, A., Yang, C., Altelaar, A. F. M., Vocking, K., Post, J. A., Harterink, M., Kapitein, L. C., Akhmanova, A., & Hoogenraad, C. C. (2019). Feedback-Driven Assembly of the Axon Initial Segment. Neuron, 104(2), 305-321.e8. https://doi.org/10.1016/j.neuron.2019.07.029