Molecular Biology of Neural Development
The brain is composed of billions of neurons that form a complex network. Inappropriate wiring of these neuronal connections has serious consequences for the sensory, motor and cognitive functions of the nervous system. Frédéric Charron’s research focuses on neural development and associated pathologies. He is a leader in Sonic hedgehog (Shh) signaling, having identified an axon pathfinding role for Shh and characterized a novel, non-canonical Shh signaling pathway. He has also characterized novel Shh receptors, a discovery that has fundamental implications for many pathologies, such as pediatric brain tumors.
During embryonic development, neurons extend axons, which are guided to their target via attractive and repulsive guidance molecules. We have demonstrated that Shh acts as a chemoattractive molecule for the axons of certain neurons in the spinal cord. One of the laboratory's objectives is to identify and characterize the components of the Shh signalling pathway in axonal guidance. In addition to helping understand the immense complexity underlying the wiring of the nervous system, this work will help to identify novel strategies to promote the proper guidance and rewiring of axons damaged by neurodegenerative diseases and brain or spinal cord injuries.
Shh is a multi-functional protein and, in addition to guiding axons, it is also a morphogen which stimulates the proliferation of granule cell precursors in the cerebellum. Abnormal regulation of Shh signaling in the cerebellum leads to medulloblastoma, a pediatric cancer of the brain that is the most common solid tumor in children. The research unit focuses on understanding how medulloblastoma forms, in particular which genes may promote or inhibit medulloblastoma tumorigenesis. This work may lead to the development of novel and more effective targeted therapies to treat medulloblastoma, and improve the survival and quality of life of affected patients.
- Director, Molecular Biology of Neural Development Research Unit, IRCM
- Full IRCM Research Professor
- Full Research Professor, Department of Medicine (accreditation in molecular biology), Université de Montréal
- Adjunct Professor, Department of Medicine (Division of Experimental Medicine), Department of Anatomy and Cell Biology, McGill University
- Canada Research Chair (Tier 1) in Developmental Neurobiology
- Faculty Member, Neurodevelopment Section, Faculty of 1000 Prime
- Member, McGill Integrated Program in Neuroscience, McGill University
- Member, Montreal Regional Brain Tumor Research Group, Montreal Neurological Institute, McGill University
- Member, Centre of Excellence in Neuroscience of Université de Montréal
Awards and honours
- 2017 Marcel-Piché Award, IRCM
- 2016 Member, College of the Royal Society of Canada
- 2013 André-Dupont Award, Club de recherches cliniques du Québec
- 2012 Young Investigator Award, Canadian Association for Neuroscience
- 2011-2012 PhD Professor and Researcher of the year, Department of Medicine, Université de Montréal
- 2010 Pierre-Bois Excellence Award, IRCM Foundation
- 2005 Peter-Lougheed-CIHR New Investigator Award
Degrees and relevant experience
- B.Sc. in biochemistry, Department of Biochemistry, Université de Montréal
- PhD in experimental medicine, Department of Medicine, McGill University
- Postdoctoral fellowship, Department of Biological Sciences, Stanford University, California, USA
- Beckman Senior Research Fellow, Department of Biological Sciences, Stanford University, California, USA
Axon guidance and nervous system circuit formation
Shh signaling and the pediatric brain tumor medulloblastoma
Approach: Cultivating cells or neural primary tissues in vitro
Approach: Mouse genetics as a model for the study of the molecular mechanisms of axon guidance or medulloblastoma formation.
Approach: Studying the development of neural circuits in vivo in mice with the help of genetically-encoded fluorescent proteins.
Approach: Complementing the mouse genetics, we also utilise CRISPR-Cas9 and in utero electroporation to manipulate genes directly in the cerebellum during development.
Ferent J, Constable S, Gigante ED, Yam PT, Mariani LE, Legué E, Liem Jr. KF, Caspary T*, Charron F*. The ciliary protein Arl13b functions outside of the primary cilium in Shh mediated axon guidance. Cell Reports Volume 29, Issue 11, 10 December 2019, Pages 3356-3366.e3 *These authors contributed equally, co-corresponding authors.
Accogli A#, Calabretta S#, St-Onge J, Boudrahem-Addour N, Dionne-Laporte A, Joset P, Azzarello-Burri S, Rauch A, Krier J, Fieg E, Pallais JC, Undiagnosed Diseases Network, McConkie-Rosell A, McDonald M, Freedman SF, Rivière J-B, Lafond-Lapalme J, Simpson BN, Hopkin RJ, Trimouille A, Van-Gils J, Begtrup A, McWalter K, Severino M, Rouleau GA, Yam PT, Charron F*, Srour M*. De novo pathogenic variants in N-cadherin cause ACOG, a syndromic neurodevelopmental disorder with agenesis of the corpus callosum and axon pathfinding, cardiac, ocular and genital defects. American Journal of Human Genetics Volume 105, Issue 4, 3 October 2019, Pages 854-868 # Equal contribution * Co-corresponding authors
Ferent J, Giguère F, Jolicoeur C, Morin S, Michaud JF, Makihara S, Yam PT, Cayouette M, Charron F. Boc Acts via Numb as a Shh-Dependent Endocytic Platform for Ptch1 Internalization and Shh-Mediated Axon Guidance. Neuron. 2019 Apr 24. pii: S0896-6273(19)30338-1. doi: 10.1016/j.neuron.2019.04.003. [Epub ahead of print]
Wu Z*, Makihara S*, Yam PT*, Teo S*, Renier N*, Balekoglu N, Moreno-Bravo JA, Olsen O, Chédotal A, Charron F# and Tessier-Lavigne M#. Long-Range Guidance of Spinal Commissural Axons by Netrin1 and Sonic Hedgehog from Midline Floor Plate Cells. Neuron. 2019 Feb 20;101(4):635-647.e4. doi: 10.1016/j.neuron.2018.12.025. Epub 2019 Jan 17.
* Ces auteurs ont contribué de façon égale à cet article #Co-auteurs principaux de correspondance / *Equal contribution #Co-senior authors
Brennan-Crispi DM, Overmiller AM, Tamayo-Orrego L, Marous MR, Sahu J, McGuinn KP, Cooper F, Georgiou IC, Frankfurter M, Salas-Alanis JC, Charron F, Millar SE, Mahoney MG, Riobo-Del Galdo NA. Overexpression of Desmoglein 2 in a mouse model of Gorlin syndrome enhances spontaneous basal cell carcinoma formation through STAT3-mediated Gli1 expression. J Invest Dermatol. 2019 Feb;139(2):300-307. doi: 10.1016/j.jid.2018.09.009. Epub 2018 Oct 3.
Peng J*, Ferent J*, Li Q*, Liu M, Da Silva RV, Zeilhofer HU, Kania A, Zhang Y#, and Charron F#. Loss of Dcc in the spinal cord is sufficient to cause a deficit in lateralized motor control and the switch to a hopping gait. Developmental Dynamics. 2018 Apr;247(4):620-629. doi: 10.1002/dvdy.24549. Epub 2018 Feb 5.
* Ces auteurs ont contribué de façon égale à cet article # Co-auteurs de correspondance / *Equal contribution #Co-corresponding authors
L'Actualité - Frédéric Charron and his team have recently shed light on a system that tells our neurons how to build the delicate circuits of our nervous system.
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