MDPTAR · Microtubule Dynamics and Protein Trafficking in Axon Regeneration

Microtubule Dynamics and Protein Trafficking in Axon Regeneration

Introduction Damage to nerves can result in numerous debilitating conditions such as spinal cord injury (SCI). However, the response of nerves to injury and the molecular processes of repair/regeneration are poorly understood, requiring new scientific approaches to determine mechanism, with the ultimate goal being improved medical outcomes. Injured axons undergo a series of processes involving retraction, terminal enlargement formation, growth cone re-formation and finally axon extension. This is achieved by the remodelling of the axonal microtubule (MT) cytoskeleton. Structural changes in the cytoskeleton partly involve the break-down and re-polymerisation of MTs as well as the post-translational modification (PTM) of MTs. These PTMs report on the different levels of stability of the MT network and direct the transport and localisation of motor proteins and cargoes into dendrites and/or axons in polarised neurons. In addition, it appears that the correct level of MT stabilisation in vitro and in vivo enables axon regrowth after injury. Until now, effort has focused on understanding MT dynamics in neuronal development and polarisation. However, the role of MT dynamics in axonal regeneration has received less attention. Therefore, our proposed study investigating MT-dependent mechanisms before and after axonal injury is crucial in determining the intrinsic ability of axons to regenerate. Therefore, understanding the fundamental role of MT cytoskeleton dynamics in axon regeneration will provide new targets for improving nerve repair. Objectives The goal of this project is to investigate the intrinsic processes and mechanisms that underlie axon regeneration in neurons of the peripheral nervous system with the hope of improving axonal regeneration in the central nervous system in conditions such as SCI. This project fits very well within European priorities for scientific research in biomedical sciences due to the relevance of nerve injury in human disease, which in the European Union leads to considerable costs for the society and individuals. Results Axon regeneration after injury requires the extensive reconstruction, reorganization and stabilization of the microtubule cytoskeleton in the growth cones. Here, we identify KIF3C as a key regulator of axonal growth and regeneration by controlling microtubule dynamics and organization in the growth cone. KIF3C is developmentally regulated. Rat embryonic sensory axons and growth cones contain undetectable levels of KIF3C protein that is locally translated immediately after injury. In adult neurons KIF3C is axonally transported from the cell body and is enriched at the growth cone where it preferentially binds to tyrosinated microtubules. Functionally, the interaction of KIF3C with EB3 is necessary for its localization at the microtubule plus-ends in the growth cone. Depletion of KIF3C in adult neurons leads to an increase in stable, overgrown and looped microtubules due to a strong decrease in the microtubule frequency of catastrophes suggesting that KIF3C functions as a microtubule destabilizing factor. Adult axons lacking KIF3C, by RNA interference or KIF3C gene knockout, display an impaired axonal outgrowth in vitro and a delayed regeneration after injury both in vitro and in vivo. Murine KIF3C knockout embryonic axons grow normally but do not regenerate after injury since they are unable to locally translate KIF3C. These data show that KIF3C is an injury-specific kinesin that contributes to axon growth and regeneration by regulating and organizing the microtubule cytoskeleton in the growth cone. Conclusions and socio-economic impact One main factor appears to underlie the successful axon regeneration program. This is the achievement of the correct balance between microtubule stabilization/destabilization. This project, has enhanced the overall competitiveness of European science in the key fields of neuroscience and the MT cytoskeleton. Drugs will be developed based on the project, which could potentially be of great medical and financial benefit to the EU. By understanding the mechanisms of MT dynamics and axonal regeneration in these neurological conditions, it becomes more feasible to design drugs or strategies to promote such regeneration and decrease morbidity and mortality from affected patients, therefore contributing to the health of EU citizens. Such drugs will have a huge economic market (billions of euros).

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз