Developmental Biology - Neurons|
The Hansel and Gretel of neuron connection
Building the delicate circuitry of our nervous system...
Our nerves consist of small cables responsible for circulating information to every part of our body, allowing us, for example, to move. These cables are actually cells called neurons with long extensions called axons.
Frédéric Charron, a researcher at the Montreal Clinical Research Institute (IRCM) and a molecular biology professor at Université de Montréal, along with his team have recently shed light on a system that tells our neurons how to build the delicate circuitry of our nervous system. The discovery by these researchers, all from the IRCM, appeared in the prestigious journal Neuron. This work may one day contribute to the development of treatments for people with a spinal cord injury or a genetic disorder affecting their motor function.
"The way each neuron is guided toward its target is critical, as all of our five senses and motor function rely on this network and its organization. A bad connection can lead to cognitive, motor or sensory disorders."
Frédéric Charron PhD, Director, Molecular Biology of Neural Development Research Unit at Montreal Clinical Research Institute (IRCM).
To grow correctly and connect to the right targets, neurons rely on 'signals' that guide them along the right path, much like a GPS. Dr. Charron's group is particularly interested in one of them: Sonic hedgehog (Shh).
Similar to a magnet, Sonic hedgehog (Shh) attracts the extension of the neuron called the axon, by binding to a receptor on its surface — a molecule named 'Boc'. Until now, scientists did not know how Shh acted on its receptor. Frédéric Charron's team demonstrates how the Boc receptor directs the axon to move through the system.
"It's as if Shh molecules are breadcrumbs that guide the axon. When the Boc receptor detects them, the membrane at the end of the axon "gobbles" up the Shh, penetrating the axon inwardly in a process called endocytosis."
Julien Ferent, postdoctoral fellow and first author on the article.
The axon then continues along its path toward places where Shh is present in higher concentration.
The efforts of IRCM researchers make it possible to more easily understand how the nervous system forms as axons follow Boc. Their breakthrough could, for example, contribute to the creation of tools in regenerative medicine which might reconstitute nervous circuits otherwise damaged by accident and causing paralysis.
• Sonic hedgehog (Shh) induces endocytosis of Boc and Ptch1 into Rab5 endosomes
• The endocytic adaptor Numb binds to Boc and is required for Boc endocytosis
• Numb is required for Shh-mediated axon attraction in vitro and axon guidance in vivo
• Binding of Shh to Boc is required for Ptch1 endocytosis and Shh axon attraction
During development, Shh attracts commissural axons toward the floor plate through a non-canonical, transcription-independent signaling pathway that requires the receptor Boc. Here, we find that Shh induces Boc internalization into early endosomes and that endocytosis is required for Shh-mediated growth-cone turning. Numb, an endocytic adaptor, binds to Boc and is required for Boc internalization, Shh-mediated growth-cone turning in vitro, and commissural axon guidance in vivo. Similar to Boc, Ptch1 is also internalized by Shh in a Numb-dependent manner; however, the binding of Shh to Ptch1 alone is not sufficient to induce Ptch1 internalization nor growth-cone turning. Therefore, the binding of Shh to Boc is required for Ptch1 internalization and growth-cone turning. Our data support a model where Boc endocytosis via Numb is required for Ptch1 internalization and Shh signaling in axon guidance. Thus, Boc acts as a Shh-dependent endocytic platform gating Ptch1 internalization and Shh signaling.
Julien Ferent, Fanny Giguère, Christine Jolicoeur, Steves Morin, Jean-Francois Michaud, Shirin Makihara, Patricia T. Yam, Michel Cayouette and Frederic Charron.
The study was carried out by Dr. Charron's team, in collaboration with the laboratory of researcher Michel Cayouette, both from the IRCM. Julien Ferent, Fanny Giguère, Steves Morin, Jean-François Michaud, Shirin Makihara, Patricia T. Yam and Frédéric Charron, from the Molecular Biology of Neural Development Research Unit at the IRCM, took part in the work. Christine Jolicoeur and Michel Cayouette, from the IRCM's Cellular Neurobiology Research Unit, also contributed to the research.
This research received financial support from the W. Garfield Weston Foundation, Brain Canada Foundation, Canada Foundation for Innovation, Canada Research Chairs Program, Fonds de recherche du Québec - Santé, Foundation for Medical Research and Canadian Institutes of Health Research.
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Shh molecules guide development of the axon. When the Boc receptor detects Shh, the membrane at the end of the axon "eats" Shh, penetrating the axon inwardly (endocytosis
). The axon then continues toward locations where Shh is higher and higher in concentration. CREDIT IRCM.