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Research unit director

I. Axon guidance and nervous system circuit formation.

The brain is composed of billions of neurons that must connect with an appropriate set of target cells to form the neuronal circuits that underlie its function. Inappropriate wiring of these neuronal connections during development leads to abnormalities affecting the sensory, motor and cognitive functions of the nervous system. Similarly, the failure of axons damaged by neurodegenerative diseases, stroke, or brain and spinal cord injuries to regenerate and reintegrate neuronal circuits seriously impacts on the life of affected individuals and causes death.

Neuronal connections form during embryonic development when neurons send out axons, tipped at their leading edge by the growth cone, which migrates through the embryonic environment to its synaptic targets. Axons extend to the vicinity of their appropriate target regions in a highly stereotyped and directed manner by detecting a variety of attractive and repulsive molecular guidance cues presented by cells in the environment. The molecules controlling neuron type specification and axon guidance have been traditionally thought to be very different and to have unrelated modes of action. However, our work indicates that they might not be so different as we found that a molecule called Sonic Hedgehog (Shh) – well known for its role in neuron type specification – also serves to guide growing axons. We have found that Shh guides commissural axons of the spinal cord and visual system axons. But how can a single molecule, like Shh, direct both neuron type specification and axon guidance? While the genes involved in neuron type specification by Shh are relatively well known, the genes involved in axon guidance by Shh are not.

Thus, one of our goals is to identify the genes involved in axon guidance by Shh and characterize how they function to guide axons. In parallel to these studies, we are using innovative genetic and live imaging approaches to characterize, with high spatio-temporal resolution, the role of axon guidance molecules, including Shh, in neural circuit formation.

II. Shh signaling and the pediatric brain tumor medulloblastoma.

In addition to our axon guidance research, we are also interested in other aspects of Shh signaling, including mechanisms underlying the reception of the Shh signal. In this regard, we have identified Boc, Cdon, and Gas1 as essential co-receptors for canonical Shh signaling. This breakthrough has fundamental implications for diseases that result from aberrant Shh signaling, including cancers and developmental disorders. Indeed, we have found that inhibition of Boc helps prevent the formation of medulloblastoma, a pediatric brain tumor. This highlight how abnormal regulation of Shh signaling in the cerebellum can lead to medulloblastoma. We have also discovered that evasion of cellular senescence is an important step in medulloblastoma progression. We are currently interested in the understanding what are the molecular and cellular changes that promote medulloblastoma development.

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