ADF/Cofilin-Mediated Actin Turnover Promotes Axon Regeneration in the Adult CNS

• Published in: Neuron (Cambridge, Mass.) Vol. 103; no. 6; pp. 1073 - 1085.e6
• Main Authors: Tedeschi, Andrea, Dupraz, Sebastian, Curcio, Michele, Laskowski, Claudia J., Schaffran, Barbara, Flynn, Kevin C., Santos, Telma E., Stern, Sina, Hilton, Brett J., Larson, Molly J.E., Gurniak, Christine B., Witke, Walter, Bradke, Frank
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.09.2019; Elsevier Limited
• Subjects: Actin; actin dynamics; Actins - metabolism; ADF/cofilin; Animals; axon injury; axon regeneration; Axons; Axons - metabolism; Axons - pathology; Cofilin; Cofilin 1 - genetics; Cofilin 1 - metabolism; Cofilin 2 - genetics; Cofilin 2 - metabolism; conditioning; Destrin - genetics; Destrin - metabolism; Developmental plasticity; Embryogenesis; Genetic transformation; Growth Cones - metabolism; Growth Cones - pathology; Immunoglobulins; Intravital Microscopy; Mice; Microscopy; Microscopy, Confocal; Molecular modelling; Morphology; Nerve Regeneration - genetics; Neurons; Neurons - metabolism; Neurons - pathology; Rats; Regeneration; Spinal cord injuries; Spinal Cord Injuries - genetics; Spinal Cord Injuries - metabolism; Spinal Cord Injuries - pathology; Statistical analysis; Time-Lapse Imaging; Trauma; Variance analysis; axon regeneration; actin dynamics; ADF/cofilin; conditioning; axon injury
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2019.07.007

Injured axons fail to regenerate in the adult CNS, which contrasts with their vigorous growth during embryonic development. We explored the potential of re-initiating axon extension after injury by reactivating the molecular mechanisms that drive morphogenetic transformation of neurons during development. Genetic loss- and gain-of-function experiments followed by time-lapse microscopy, in vivo imaging, and whole-mount analysis show that axon regeneration is fueled by elevated actin turnover. Actin depolymerizing factor (ADF)/cofilin controls actin turnover to sustain axon regeneration after spinal cord injury through its actin-severing activity. This pinpoints ADF/cofilin as a key regulator of axon growth competence, irrespective of developmental stage. These findings reveal the central role of actin dynamics regulation in this process and elucidate a core mechanism underlying axon growth after CNS trauma. Thereby, neurons maintain the capacity to stimulate developmental programs during adult life, expanding their potential for plasticity. Thus, actin turnover is a key process for future regenerative interventions. [Display omitted] •Elevated actin turnover is essential for regenerative growth•ADF/cofilin activity increases during conditioning-mediated regeneration•ADF/cofilin is necessary and sufficient for axon regeneration•The severing activity of ADF/cofilin is critical for axon regeneration Tedeschi et al. identify ADF/cofilin as a key driver of axon regeneration in adult dorsal root ganglion neurons. Specifically, enhanced actin turnover by the ADF/cofilin severing function controls axon regeneration in the adult CNS.