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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2018.00357

Tropomodulin's actin-binding abilities are required to modulate dendrite development

 Kevin T. Gray1, 2,  Holly Stefen3, Christopher J. Keller1, 2, Thu Ly2,  Mert Colpan2, Gary A. Wayman4, Edward Pate2,  Thomas Fath3, 5* and  Alla S. Kostyukova1, 2
  • 1Voiland School of Chemical Engineering and Bioengineering, Washington State University, Pullman, United States
  • 2Voiland School of Chemical Engineering and Bioengineering, Washington State University, Pullman, United States
  • 3University of New South Wales, Australia
  • 4Integrative Physiology and Neuroscience, College of Veterinary Medicine, Washington State University, United States
  • 5Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, Macquarie University, Australia

There are many unanswered questions about the roles of the actin pointed end capping and actin nucleation by tropomodulins (Tmod) in regulating neural morphology. Previous studies indicate that Tmod1 and Tmod2 regulate morphology of the dendritic arbor and spines. Tmod3, which is expressed in the brain, had only a minor influence on morphology. Although these studies established a defined role of Tmod in regulating dendritic and synaptic morphology, the mechanisms by which Tmods exert these effects are unknown. Here, we overexpressed a series of mutated forms of Tmod1 and Tmod2 with disrupted actin-binding sites in hippocampal neurons and found that Tmod1 and Tmod2 require both of their actin-binding sites to regulate dendritic morphology and dendritic spine shape. Proximity ligation assays indicate that these mutations impact the interaction of Tmod1 and Tmod2 with tropomyosins Tpm3.1 and Tpm3.2. This impact on Tmod/Tpm interaction may contribute to the morphological changes observed. Finally, we use molecular dynamics simulations to characterize the structural changes, caused by mutations in the C-terminal helix of the leucine-rich repeat (LRR) domain of Tmod1 and Tmod2 alone and when bound onto actin monomers. Our results expand our understanding of how neurons utilize the different Tmod isoforms in development.

Keywords: Neurite outgrowth, Actin Cytoskeleton, Hippocampal neuron culture, Tropomodulin, actin dynamics

Received: 17 Jun 2018; Accepted: 11 Sep 2018.

Edited by:

Jaewon Ko, Daegu Gyeongbuk Institute of Science and Technology (DGIST), South Korea

Reviewed by:

Dongmin Lee, Korea University, South Korea
Michael E. Cahill, University of Wisconsin-Madison, United States  

Copyright: © 2018 Gray, Stefen, Keller, Ly, Colpan, Wayman, Pate, Fath and Kostyukova. 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) and the copyright owner(s) 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: Dr. Thomas Fath, University of New South Wales, Sydney, Australia, t.fath@unsw.edu.au