Team "Central nervous system: From development to repair" *

Themes of research

Impairment of the CNS often affects vital functions such as vision, in the case of glaucoma, or motor function, in the cases of multiple sclerosis or spinal cord injuries. Most of the patients suffering from CNS injuries must endure irreversible disabilities as a result of these insults. Moreover, injuries to the spinal cord often affect young adults, who will have to deal with severe disabilities for the rest of their lives. The main cause for a lack of efficient treatment is that unlike young neurons, mature neurons from the CNS lose the ability to regenerate their axons after injury. Thus understanding the detailed mechanisms of neuronal growth, repair and functional recovery remains not only one of the greatest questions of neurobiology but represents also a major challenge for public health and society.

The team addresses this question by two different and complementary angles:

• Guidance of regenerative fibers
  Manipulating extrinsic factors failed to reach the expected regeneration. However modulating intrinsic pathways has shown promising results. Particularly, our work demonstrated that the simultaneous activation of mTOR, JAK/STAT and c-myc pathways allows exceptional regeneration with axons close to their targets. However it also exacerbates previously described phenomenon of misguidance with potential aberrant circuit formation. In this context, we address the yet unexplored problem of the guidance of regenerating axons in adults in order to promote the formation of a functional new circuit after injury. Indeed what are the modalities of guidance in the adult? Are axons still responsive to developmental guidance cues and are they still expressed? Can regenerative axons form connections with their targets and are these connections functional?
  To answer these critical questions, we use the combination of state of the art biochemistry, imaging, and electrophysiology in an in-vivo and ex-vivo model of the visual system to 1) Understand axon guidance in mature system in order to properly drive regenerative axons to their brain targets and avoid aberrant projections, and 2) Analyze the formation of a functional optic nerve circuit after injury.  

• Mechanisms to promote regeneration
  The absence of treatment to overcome CNS regenerative failure is pointing out our lack of knowledge in the detailed mechanisms of neuronal growth, repair and their fine-tuning during development and injury. We believe that the translation machinery holds the key to unlock the regenerative failure of central nervous system.
  Indeed, what are the modifications of the translational apparatus in mature neurons or induced by injury? Which mRNAs are specifically controlled by this mechanism? And finally is manipulating translational complex sufficient to promote neuron survival and regeneration?
  To answer these critical questions, we use a combination of in-vivo models of neuronal development, CNS injury (optic nerve and spinal cord), high throughput analysis and biochemistry, to 1) Define the structure of the translational machinery 2) determine the role of specialized complex in translation regulation 3) modulate the translational code to promote CNS neurons survival and regeneration.

Techniques utilisées :

• Mice models (transgenic mice, optic nerve and spinal cord surgeries)
• Molecular Biology/Virus engineering & production
• Histology: Immunohistochemistry; Immunofluorescence; In situ hybridization
• Biochemistry: Immunoprecipitation, western-blot
• Mass Spectrometry and RNA analysis
• Cell Biology: Explant culture/Microfluidics chambers; primary neuron culture; cell lines culture.
• Microscopy: Epifluorescence; Spinning disc; Confocal; Light Sheet.

Partners :