Dynein Regulator NDEL1 Controls Polarized Cargo Transport at the Axon Initial Segment

• Published in: Neuron (Cambridge, Mass.) Vol. 89; no. 3; pp. 461 - 471
• Main Authors: Kuijpers, Marijn, van de Willige, Dieudonnée, Freal, Amélie, Chazeau, Anaël, Franker, Mariella A., Hofenk, Jasper, Rodrigues, Ricardo J. Cordeiro, Kapitein, Lukas C., Akhmanova, Anna, Jaarsma, Dick, Hoogenraad, Casper C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.02.2016; Elsevier Limited
• Subjects: Animals; Ankyrin-G; Ankyrins - metabolism; axon initial segment; Axons - metabolism; cargo trafficking; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cytoskeleton; Cytoskeleton - metabolism; dynein; Dyneins - metabolism; Experiments; Localization; Mass spectrometry; Mice; Mice, Knockout; NDE1; NDEL1; neuron; Neurons; NudE; polarized transport; Protein Transport; Proteins; R&D; Regulation; Research & development; Scientific imaging; Synaptic Vesicles - metabolism; dynein; axon initial segment; polarized transport; cargo trafficking; NDE1; neuron; Ankyrin-G; NudE; NDEL1
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2016.01.022

The development and homeostasis of neurons relies heavily on the selective targeting of vesicles into axon and dendrites. Microtubule-based motor proteins play an important role in polarized transport; however, the sorting mechanism to exclude dendritic cargo from the axon is unclear. We show that the dynein regulator NDEL1 controls somatodendritic cargo transport at the axon initial segment (AIS). NDEL1 localizes to the AIS via an interaction with the scaffold protein Ankyrin-G. Depletion of NDEL1 or its binding partner LIS1 results in both cell-wide and local defects, including the non-polarized trafficking of dendritic cargo through the AIS. We propose a model in which LIS1 is a critical mediator of local NDEL1-based dynein activation at the AIS. By localizing to the AIS, NDEL1 facilitates the reversal of somatodendritic cargos in the proximal axon. •NDEL1 redistributes from the centrosome to the AIS during neurodevelopment•Dynein regulator NDEL1 stably binds to Ankyrin-G at the AIS•The motor protein dynein drives transport of somatodendritic cargo out of the AIS•Accumulation of NDEL1 at the AIS is necessary for efficient local cargo reversal Polarized cargo transport ensures the sorting of vesicles specifically into the axon or dendrites. Kuijpers et al. reveal a critical role for dynein regulator NDEL1 as a gatekeeper of somatodendritic cargos at the axon initial segment.