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ORIGINAL RESEARCH article

Front. Neurosci.
Sec. Neurodevelopment
Volume 18 - 2024 | doi: 10.3389/fnins.2024.1436312
This article is part of the Research Topic Neuronal Guidance Signaling in Health and Neurological Diseases View all articles

Navigating the Tubulin Code: Netrin-1 requires TTLL1 to stimulate axon growth

Provisionally accepted
Kyle Northington Kyle Northington 1Jasmynn Calderon Jasmynn Calderon 2Emily Bates Emily Bates 1*
  • 1 Section of Developmental Biology, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • 2 Department of Pediatrics, University of Colorado, Colorado, United States

The final, formatted version of the article will be published soon.

    In the developing brain, neurons extend an axonal process through a complex and changing environment to form synaptic connections with the correct targets in response to extracellular cues. Microtubule and actin filaments provide mechanical support and drive axon growth in the correct direction. The axonal cytoskeleton responds to extracellular guidance cues.Netrin-1 is a multifunctional guidance cue that can induce alternate responses based on the bound receptor. The mechanism by which actin responds to Netrin-1 is well described. However, how Netrin-1 influences the microtubule cytoskeleton is less understood. Appropriate microtubule function is required for axon pathfinding, as mutations in tubulin phenocopy axon crossing defects of Netrin-1 and DCC mutants. Microtubule stabilization is required for attractive guidance cue response. The C-terminal tails of microtubules can be post-translationally modified. Post-translational modifications (PTMs) help control the microtubule cytoskeleton.We measured polyglutamylation in cultured primary mouse cortical neurons before and after Netrin-1 stimulation. We used immunohistochemistry to measure how Netrin-1 stimulation alters microtubule-associated protein localization. Next, we manipulated TTLL1 to determine if Netrin-1-induced axon growth and MAP localization depend on polyglutamylation levels.In this study, we investigated if Netrin-1 signaling alters microtubule PTMs in the axon.We found that microtubule polyglutamylation increases after Netrin-1 stimulation. This change in polyglutamylation is necessary for Netrin-1-induced axonal growth rate increases. We next determined that MAP1B and DCX localization changes in response to Netrin-1. These proteins can both stabilize the microtubule cytoskeleton and may be responsible for Netrin-1-induced growth response in neurons. The changes in DCX and MAP1B depend on TTLL1, a protein responsible for microtubule polyglutamylation.

    Keywords: microtubule polyglutamylation, microtubule associated protein 1B, DCX = doublecortin, Netrin 1, Axon growth and guidance, Tubulin (Microtubules)

    Received: 21 May 2024; Accepted: 18 Sep 2024.

    Copyright: © 2024 Northington, Calderon and Bates. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Emily Bates, Section of Developmental Biology, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, 80045, Colorado, United States

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