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Giant ankyrin-B mediates transduction of axon guidance and collateral branch pruning factor Sema 3A

Blake A. Creighton, View ORCID ProfileDeepa Ajit, Simone Afriyie, Julia Bay, View ORCID ProfileDamaris Lorenzo
doi: https://doi.org/10.1101/2021.05.03.442401
Blake A. Creighton
1Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Deepa Ajit
1Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Simone Afriyie
1Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Julia Bay
1Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Damaris Lorenzo
1Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
2Carolina Institute for Developmental Disabilities, Chapel Hill, NC, USA
3Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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  • For correspondence: damaris_lorenzo@med.unc.edu
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Abstract

Variants in the high confident autism spectrum disorder gene ANK2 target both ubiquitously expressed 220-kDa ankyrin-B and neurospecific 440-kDa ankyrin-B (AnkB440) isoforms. Previous work showed that knock-in mice expressing an ASD-linked Ank2 variant yielding a truncated AnkB440 product exhibit ectopic brain connectivity and behavioral abnormalities. Expression of this variant or loss of AnkB440 caused axonal hyperbranching in vitro, which implicated AnkB440 microtubule bundling activity in suppressing collateral branch formation. Leveraging multiple mouse models, cellular assays, and live microscopy, we show that AnkB440 also modulates axon collateral branching stochastically by reducing the number of F-actin-rich branch initiation points. Additionally, we show that AnkB440 enables growth cone (GC) collapse in response to chemorepellent factor semaphorin 3A (Sema 3A) by stabilizing its receptor complex L1 cell adhesion molecule/neuropilin-1. ASD-linked ANK2 variants failed to rescue Sema 3A-induced GC collapse. We propose that impaired response to repellent cues due to AnkB440 deficits leads to axonal guidance and branch pruning defects and may contribute to the pathogenicity of ANK2 variants.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted May 03, 2021.
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Giant ankyrin-B mediates transduction of axon guidance and collateral branch pruning factor Sema 3A
Blake A. Creighton, Deepa Ajit, Simone Afriyie, Julia Bay, Damaris Lorenzo
bioRxiv 2021.05.03.442401; doi: https://doi.org/10.1101/2021.05.03.442401
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Giant ankyrin-B mediates transduction of axon guidance and collateral branch pruning factor Sema 3A
Blake A. Creighton, Deepa Ajit, Simone Afriyie, Julia Bay, Damaris Lorenzo
bioRxiv 2021.05.03.442401; doi: https://doi.org/10.1101/2021.05.03.442401

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