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Vinculin mediated axon growth requires interaction with actin but not talin

Pranay Mandal, Vivek Belapurkar, Deepak Nair, Narendrakumar Ramanan

Posted on: 4 August 2020

Preprint posted on 3 July 2020

Article now published in Cellular and Molecular Life Sciences at http://dx.doi.org/10.1007/s00018-021-03879-7

Vinculin is essential for axon growth and neuronal migration, but structure/function mutants reveal various requirements.

Selected by Amanda Haage

Why This is Cool – Axon growth, migration, and guidance are necessary developmental processes to form our neural circuits and the misregulation of these processes is linked to multiple neural disorders. This study looks at a missing piece of the basic cell biology behind this process using genetic structure/function mutants, in vitro cultures, and embryonic/neonatal mouse models. Their first result starts with a traditional knockout approach where they demonstrate that vinculin is necessary for axon growth and migration. Vinculin is another adaptor protein functioning in both cell-cell and cell-extracellular matrix (ECM) adhesion, very similarly and cooperatively with my love, talin. The interaction between vinculin and talin has been investigated recently and shown to be specifically important for mechanosensing (1). The authors then go several steps further by investigating the impact of numerous functional mutants on axon growth and migration. These are summarized in the table below. Subjectively, the most interesting part of these results is that disrupting the talin binding site in vinculin (A50I mutant) had no effect on these processes. This seems contrary to a lot of studies that demonstrate how these proteins work together and contrary to a previously established role of talin in axon regeneration (2). Another interesting part of this study is the results using the vinculin autoinhibition mutant (Vcl-T12). Vinculin, like talin, can exist in a closed conformation, where the head binds the tail, masking important binding sites and hyperactivation caused by disrupting this interaction is detrimental to morphogenesis (3). Here they show that hyperactive vinculin increases axon growth and migration, providing an opposite result to many of their other mutants. Lastly, the authors explore the tail only mutants in more detail, showing that they may increase actin binding too far, as an actin binding mutant can rescue many of the effects.

Mutant Potential Function Axon Growth Migration Branching
Vcl-FL Full Length Same Same N/A
Vcl-258 Lacks Tail Decreased Same N/A
Vcl-851 Lacks Tail Decreased Same N/A
Vcl-T Tail Only Decreased* Decreased Increased
Vcl-T12 Autoinhibition Loss Increased* Increased/Same N/A
Vcl-LD PIP2 Binding Loss Decreased Same N/A
Vcl-FL (A50I) Talin Binding Loss Same Same N/A
Vcl-FL (I997A) Actin Binding Loss Decreased Same/Rescue Same/Rescue

Table 1: Summary of results for each point mutation studied. * confirmed by in vivo model

 

Why I Selected It – I came for the talin mention in the title, but stayed for the structure/function analysis and super resolution microscopy. I have never worked on cultured or in vivo neurons, but it’s a consistently fascinating field for actin regulation and cell migration. I also personally think these kinds of structure/function mutant survey papers describing proteins with a known multitude of functions do a lot of heavy lifting in their respective fields. The authors provide a great resource for others not only in the results they described, but in the detailed descriptions of mutant constructs as well.

Open Questions –

  1. How do you reconcile your talin binding negative results with the previous results that indicate a role (2)?

Related References –

  1. Vinculin & Talin
  2. Talin in Axon Regeneration
  3. Vinculin Autoinhibition

 

doi: https://doi.org/10.1242/prelights.23722

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1 comment

4 months

Pranay Mandal

Hello Amanda,

You have summarized the study very briefly and beautifully. I am happy that you liked the study. Your question is very valid, and even we were surprised to see the results as we expected something completely opposite. Further studies are needed to be performed to have a scientific explanation for that.

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