A functional role for Septin-2 in the maintenance of the axon initial segment and in human cognitive development
Weiss L, Pavez M, Labudina A, Andriichuk L, Jones O, Jones A, Barwick D, Jenkins Z, Basak I, Morgan T, Neuhann T, Rankin J, Giltay J, Agolini E, Novelli A, Pizzuti A, Koboldt DC, Ramadesikan S, Dublin-Ryan LB, Hughes S, Di Donato N, Gimenez G, Namba T, Gumy LF, Robertson SP (2026)
Publication Type: Journal article
Publication year: 2026
Journal
Book Volume: 149
Pages Range: 2533-2549
Journal Issue: 7
Abstract
The establishment of neuronal polarity, whereby somatodendritic and axonal cellular compartments are defined, is a critical determinant for the development of neuronal networks and patterning during neurogenesis. The axon initial segment (AIS), a key structure in the establishment of this polarity, is formed through interactions between the microtubule and actin cytoskeleton, Ankyrin G, TRIM46 and multiple transmembrane and perimembranous proteins. Here, we implicate a component of the septin cytoskeleton, Septin-2, in the maintenance and function of the AIS through the study of mutations found in five unrelated human individuals and one mother-daughter duo with a majority presenting with cognitive impairment. Septins form octameric rods that assemble into higher-order filamentous scaffolds driven by Septin-2 homodimerization. Mutant Septin-2 is predicted to impart a dominant negative blockade on septin octamers forming these structures by precluding Septin-2 homodimerization. Expression of mutant Septin-2 constructs in neurons leads to the disappearance of canonical hallmarks of the AIS. This includes loss of Ankyrin G in the AIS, aberrant localization of MAP2 within the distal axon, axonal shortening and electrophysiological hypoexcitability. We further show that Septin-2 binds to a neuron-specific domain of Ankyrin G, an interaction that is largely ablated by these mutations. These data establish a role for Septin-2 in the maintenance and function of the AIS and implicate cytoskeletal structures composed of septin oligomers in the establishment of higher cognitive functions in humans.
Involved external institutions
University of Otago
New Zealand (NZ)
Helsingin yliopisto / University of Helsinki
Finland (FI)
Medizinisch Genetisches Zentrum (MGZ) / Medical Genetics Center
Germany (DE)
University of Exeter
United Kingdom (GB)
University Medical Centre Utrecht (UMC Utrecht)
Netherlands (NL)
Ospedale Pediatrico Bambino Gesu
Italy (IT)
Università degli studi "La Sapienza"
Italy (IT)
Nationwide Children's Hospital
United States (USA) (US)
Medizinische Hochschule Hannover (MHH) / Hannover Medical School
Germany (DE)
New Zealand (NZ)
Helsingin yliopisto / University of Helsinki
Finland (FI)
Medizinisch Genetisches Zentrum (MGZ) / Medical Genetics Center
Germany (DE)
University of Exeter
United Kingdom (GB)
University Medical Centre Utrecht (UMC Utrecht)
Netherlands (NL)
Ospedale Pediatrico Bambino Gesu
Italy (IT)
Università degli studi "La Sapienza"
Italy (IT)
Nationwide Children's Hospital
United States (USA) (US)
Medizinische Hochschule Hannover (MHH) / Hannover Medical School
Germany (DE)
How to cite
APA:
Weiss, L., Pavez, M., Labudina, A., Andriichuk, L., Jones, O., Jones, A.,... Robertson, S.P. (2026). A functional role for Septin-2 in the maintenance of the axon initial segment and in human cognitive development. Brain, 149(7), 2533-2549. https://doi.org/10.1093/brain/awaf468
MLA:
Weiss, Luisa, et al. "A functional role for Septin-2 in the maintenance of the axon initial segment and in human cognitive development." Brain 149.7 (2026): 2533-2549.
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