2. Academic Validation
  3. Reticulon-1 synthesis controls outgrowth and microtubule dynamics in injured cortical axons

Reticulon-1 synthesis controls outgrowth and microtubule dynamics in injured cortical axons

  • Life Sci Alliance. 2026 Jan 16;9(4):e202503571. doi: 10.26508/lsa.202503571.
Alejandro Luarte 1 2 3,  Javiera Gallardo 4,  Daniela Corvalán 5 2,  Ankush Chakraborty 5 2,  Cláudio Gouveia Roque 6,  Francisca Bertin 7,  Carlos Contreras 5 2,  Juan Pablo Ramírez 5 2,  André Weber 8,  Waldo Acevedo 9,  Werner Zuschratter 10 8,  Rodrigo Herrera-Molina 11 12,  Úrsula Wyneken 5 2 3,  Andrea Paula-Lima 13 14,  Tatiana Adasme-Rocha 15,  Jorge Toledo 16,  Rodrigo Vergara 17,  Antonia Figueroa 5 2,  Carolina González 18,  Christian González-Billault 19 20 21 22,  Ulrich Hengst 6 23,  Andrés Couve 19
Affiliations

Affiliations

  • 1 Faculty of Medicine, Universidad de los Andes, Santiago, Chile [email protected].
  • 2 Program in Neuroscience, Center for Biomedical Research, and Innovation (CiiB), Universidad de los Andes, Santiago, Chile.
  • 3 IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile.
  • 4 Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Santiago, Chile.
  • 5 Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
  • 6 The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
  • 7 Facultad de Medicina Veterinaria y Agronomía, Universidad de Las Américas, Santiago, Chile.
  • 8 Photonscore GmbH, Magdeburg, Germany.
  • 9 Instituto de Química, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile.
  • 10 Leibniz Institute for Neurobiology, Magdeburg, Germany.
  • 11 Centro Integrativo de Biología y Química Aplicada, Universidad Bernardo O'Higgins, Santiago, Chile.
  • 12 Department of Pharmacology and Physiology, George Washington University, Washington, DC, USA.
  • 13 Biomedical Neuroscience Institute and Department of Neurosciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.
  • 14 Institute for Research in Dental Sciences (ICOD), Faculty of Dentistry, Universidad de Chile, Santiago, Chile.
  • 15 Oficina de Apoyo a la Investigación Clínica, Hospital Clínico Universidad de Chile, Santiago, Chile.
  • 16 Health Sciences Department, Universidad de Aysén, Coyhaique, Chile.
  • 17 Departamento de Kinesiología, Facultad de Artes y Educación Física, Universidad Metropolitana de Ciencias de la Educación, Ñuñoa, Chile.
  • 18 Latin American Brain Health Institute (BrainLat), Universidad Adolfo Ibañez, Santiago, Chile.
  • 19 Department of Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile.
  • 20 Department of Biology, Faculty of Sciences, Universidad de Chile, Santiago, Chile.
  • 21 Public Nutrition Unit, Institute for Nutrition and Food Technologies, Universidad de Chile, Santiago, Chile.
  • 22 The Buck Institute for Research on Aging, Novato, CA, USA.
  • 23 Department of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
PMID: 41545196 DOI: 10.26508/lsa.202503571
Abstract

The regenerative potential of developing cortical axons depends on intrinsic mechanisms, such as axon-autonomous protein synthesis, that are still not fully understood. An emerging factor in this regenerative response is the bidirectional interplay between microtubule dynamics and the axonal ER. We hypothesize that locally synthesized ER proteins regulate microtubule dynamics and the regeneration of cortical axons. RNA data mining identified the ER-shaping protein Reticulon-1 as a relevant candidate across eight axonal transcriptomes. Using microfluidics, we show that axonal treatment with a small RNA against Reticulon-1 mRNA (Reticulon-1 knockdown) increases outgrowth of injured cortical axons while reducing their tubulin levels. We show by live-cell imaging that axonal Reticulon-1 knockdown increases microtubule growth rate in noninjured axons and restores this parameter after injury. Axonal inhibition of the microtubule-severing protein Spastin prevents the effects of Reticulon-1 knockdown over tubulin levels and outgrowth. We provide evidence that the Reticulon-1C isoform is synthesized within axons and attenuates Spastin-mediated microtubule severing. These findings support a model in which axonal protein synthesis regulates microtubule dynamics and axon outgrowth after injury.

Figures
Products