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

Alejandro Luarte, Faculty of Medicine, Universidad de los Andes, Santiago, Chile aluarte@uandes.cl.
Javiera Gallardo, Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Santiago, Chile.
Daniela Corvalán, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
Ankush Chakraborty, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
Cláudio Gouveia Roque, 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.
Francisca Bertin, Facultad de Medicina Veterinaria y Agronomía, Universidad de Las Américas, Santiago, Chile.
Carlos Contreras, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
Juan Pablo Ramírez, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
André Weber, Photonscore GmbH, Magdeburg, Germany.
Waldo Acevedo, Instituto de Química, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile.
Werner Zuschratter, Leibniz Institute for Neurobiology, Magdeburg, Germany.
Rodrigo Herrera-Molina, Centro Integrativo de Biología y Química Aplicada, Universidad Bernardo O'Higgins, Santiago, Chile.
Úrsula Wyneken, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
Andrea Paula-Lima, Biomedical Neuroscience Institute and Department of Neurosciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.
Tatiana Adasme-Rocha, Oficina de Apoyo a la Investigación Clínica, Hospital Clínico Universidad de Chile, Santiago, Chile.
Jorge Toledo, Health Sciences Department, Universidad de Aysén, Coyhaique, Chile.
Rodrigo Vergara, Departamento de Kinesiología, Facultad de Artes y Educación Física, Universidad Metropolitana de Ciencias de la Educación, Ñuñoa, Chile.
Antonia Figueroa, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
Carolina González, Latin American Brain Health Institute (BrainLat), Universidad Adolfo Ibañez, Santiago, Chile.
Christian González-Billault, Department of Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile.
Ulrich Hengst, 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.
Andrés Couve, Department of Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile.

Document Type

Journal Article

Publication Date

4-1-2026

Journal

Life science alliance

Volume

9

Issue

4

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.

Department

Pharmacology and Physiology

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