title: Actin turnover is required to prevent axon retraction driven by endogenous actomyosin contractility.
abstract: Growth cone motility and guidance depend on the dynamic reorganization of filamentous actin (F-actin). In the growth cone, F-actin undergoes turnover, which is the exchange of actin subunits from existing filaments. However, the function of F-actin turnover is not clear. We used jasplakinolide (jasp), a cell-permeable macrocyclic peptide that inhibits F-actin turnover, to study the role of F-actin turnover in axon extension. Treatment with jasp caused axon retraction, demonstrating that axon extension requires F-actin turnover. The retraction of axons in response to the inhibition of F-actin turnover was dependent on myosin activity and regulated by RhoA and myosin light chain kinase. Significantly, the endogenous myosin-based contractility was sufficient to cause axon retraction, because jasp did not alter myosin activity. Based on these observations, we asked whether guidance cues that cause axon retraction (ephrin-A2) inhibit F-actin turnover. Axon retraction in response to ephrin-A2 correlated with decreased F-actin turnover and required RhoA activity. These observations demonstrate that axon extension depends on an interaction between endogenous myosin-driven contractility and F-actin turnover, and that guidance cues that cause axon retraction inhibit F-actin turnover.
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D000199:Actins / Q000378:metabolism*; D000205:Actomyosin / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002642:Chick Embryo / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D047630:Depsipeptides; D036383:Ephrin-A2 / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008845:Microinjections; D018715:Microscopy, Video; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010590:Phalloidine / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D012160:Retina / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D047630:Depsipeptides; D036383:Ephrin-A2; D047908:Intracellular Signaling Peptides and Proteins; D010456:Peptides, Cyclic; C057531:jasplakinolide; D010590:Phalloidine; D000205:Actomyosin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C080215:MYLK protein, Bos taurus; D009219:Myosin-Light-Chain Kinase; D020742:rhoA GTP-Binding Protein