| Autor: |
Lemaitre D; Facultad de Medicina, Centro de Fisiología Celular e Integrativa, Universidad del Desarrollo, Santiago, Chile., Hurtado ML; The Roslin Institute, University of Edinburgh, Edinburgh, UK., De Gregorio C; Centro de Medicina Regenerativa, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago, Chile., Oñate M; Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile., Martínez G; Biomedical Neuroscience Institute (BNI), Faculty of Medicine, University of Chile, Santiago, Chile.; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Departamento de Neurología y Neurocirugía, Hospital Clínico, University of Chile, Santiago, Chile.; FONDAP Center for Geroscience (GERO) Brain Health and Metabolism, Santiago, Chile., Catenaccio A; Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile., Wishart TM; The Roslin Institute, University of Edinburgh, Edinburgh, UK., Court FA; FONDAP Center for Geroscience (GERO) Brain Health and Metabolism, Santiago, Chile. felipe.court@umayor.cl.; Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile. felipe.court@umayor.cl.; Buck Institute for Research on Aging, Novato, CA, 94945, USA. felipe.court@umayor.cl. |
| Abstrakt: |
Peripheral nerve injuries result in motor and sensory dysfunction which can be recovered by compensatory or regenerative processes. In situations where axonal regeneration of injured neurons is hampered, compensation by collateral sprouting from uninjured neurons contributes to target reinnervation and functional recovery. Interestingly, this process of collateral sprouting from uninjured neurons has been associated with the activation of growth-associated programs triggered by Wallerian degeneration. Nevertheless, the molecular alterations at the transcriptomic level associated with these compensatory growth mechanisms remain to be fully elucidated. We generated a surgical model of partial sciatic nerve injury in mice to mechanistically study degeneration-induced collateral sprouting from spared fibers in the peripheral nervous system. Using next-generation sequencing and Ingenuity Pathway Analysis, we described the sprouting-associated transcriptome of uninjured sensory neurons and compare it with the activated by regenerating neurons. In vitro approaches were used to functionally assess sprouting gene candidates in the mechanisms of axonal growth. Using a novel animal model, we provide the first description of the sprouting transcriptome observed in uninjured sensory neurons after nerve injury. This collateral sprouting-associated transcriptome differs from that seen in regenerating neurons, suggesting a molecular program distinct from axonal growth. We further demonstrate that genetic upregulation of novel sprouting-associated genes activates a specific growth program in vitro, leading to increased neuronal branching. These results contribute to our understanding of the molecular mechanisms associated with collateral sprouting in vivo. The data provided here will therefore be instrumental in developing therapeutic strategies aimed at promoting functional recovery after injury to the nervous system. |
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