Axon Guidance and Regeneration of the central nervous system – AxGaRe

Nervous system diseases represent more than 35% of Europe’s total illness burden. The impairment of central nervous system (CNS) often affects vital functions such as vision in the cases of glaucoma or motor function in the case of multiple sclerosis or spinal cord injuries. People suffering from CNS injuries must endure irreversible disabilities as a result of these insults for the rest of their lives as no treatment is available.
The main cause of the lack of recovery is that unlike young neurons, mature neurons in the CNS lose the ability to regenerate their axon after injury. Thus understanding the detailed mechanisms of neuronal growth and repair remains one of the greatest challenges of neurobiology and also for the society. Tremendous amount of work has been achieved in order to identify and characterize inhibitory molecules that prevent axonal regrowth. It is now well described that the glia scar forms a physical barrier to regenerative axons and secretes inhibitory molecules such as CSPGs. Myelin derived inhibitory factors such as Nogo also showed strong inhibitory effects. However, removing these molecules genetically or pharmacologically has failed to reach the expected level of regeneration in the models of CNS injuries. This suggests that other mechanisms are involved in the process of axon regeneration. Recently, manipulating the intrinsic neuronal growth capabilities presented promising results. Several pathways have been identified to promote extensive axon regeneration (such as PTEN, KLF transcription factors or SOCS3). My post-doctoral work showed that the simultaneous activation of mTOR, JAK/STAT c-myc pathways allows exceptional regeneration phenotype, rising up new possibilities and questions. In one hand, regenerating axons were observed close to their brain targets, allowing us to ask whether those fibers are able to reconnect neurons, form synaptic connections and relay function. In the other hand, we noted dramatic misguidance phenotypes, leading to the loss of more than 50% of growing axons and opening up the possibility for aberrant circuit formation.
In this project, we propose to take advantage of our model (mTOR and JAK/STAT pathways activation combined with c-myc overexpression) to answer these questions. The major objective of this proposal is to address axon guidance of regenerative fibers in order to build a new functional circuit. We will attempt to uncover these mechanisms by focusing on the retina ganglia cells and the visual system. Specifically, we want to 1) Understand axon guidance in mature system in order to properly drive regenerative axons to their targets in the brain. We will determine how guidance modalities are conserved and/or modulated in adult before and after injury and how intrinsic neuronal manipulation can affect these processes by using quantitative mass spectrometry of pure neuron population. 2) Analyzing the formation of a functional circuit after injury. Indeed, we can now address the critical questions of the functionality of a regenerative circuit. We will first determine whether the regenerating axons can form synapses and then by using different electrophysiological technics we will establish whether those synapses are active or not.
This proposal will lead to a better understanding of the mechanisms underlying CNS axon regeneration and functional recovery. Particularly, we will decipher for the first time guidance properties in adult and how to rebuild a functional circuit. The results obtained from this proposal will be of crucial importance for the future of the field of neurodegeneration/regeneration and to develop efficient therapeutic strategies.