Understanding how the brain works is one of the greatest questions facing biologists today. Speaking to a group of students and professors, Dr. Bryan Stewart described the formation of neural synapses, which is an interesting step in brain development. Dr. Stewart is the Canada Research Chair in Molecular Genetics of Neural Communication and Professor of Biology at the University of Toronto Mississauga. His lab is interested in how these important cellular structures of the brain and central nervous system originate.
Neural development can be divided into a number of highly controlled steps. It starts with the transformation of stem cells into neurons, the extension of axons and dendrites into the body (two cell protrusions required for neuron function), the recognition of a target cell by the neuronal axon, and finally, the formation of the synapse, where communication takes place. Each of these steps is important in the development of the brain and central nervous system. Without each one, the complex tasks the brain performs, like moving muscles, would not be possible.
Communication between a neuron and its target cell—a muscle cell, a gland cell, or another neuron—requires the release of message molecules known as neurotransmitters from the tip of the neuronal axon into a junction known as the synapse. The neurotransmitters can then diffuse across the synapse to receptors on the target cell to effect a change. For example, the release of neurotransmitters at the neuromuscular junction (NMJ) and the synapse between a motor neuron and a muscle cell causes the muscle to contract.
To determine how the neuron develops to form a complete and functional synapse between its axon and the target cell, the Stewart lab uses the fruit fly as a model. The fruit fly NMJ is remarkably similar to the NMJ of other animals, including humans.
So how does the neuron know when to make a synapse? Dr. Stewart believes that the N-Ethylmaleimide-sensitive fusion protein 2 (NSF2) is involved. NSF2 is a large protein that is ubiquitous in the fly and is a member of the large family of proteins known as the AAA ATPases. NMJs of fruit flies that have mutations in the NSF2 protein display strange morphologies: the NMJs are longer, more branched, and have a characteristic circular pattern. This observation led to the hypothesis that NSF2 may be involved in controlling how the synapse forms.
In support of this, Stewart’s group was able to show that the protein NSF2 specifically interacts with Highwire, a protein known to be involved in limiting synaptic development. Taking a multi-pronged approach involving genetics, immuno-precipitations, and fluorescence microscopy, Stewart believes that his group has shown that NSF2 is a regulator of a pathway that leads to synapse development.
He believes that NSF2 helps the protein Highwire to perform its function of controlling synapse formation. Highwire has been shown to act at the top of a complex cellular signaling pathway that is responsible for synapse formation. Highwire actually turns this pathway down and prevents synapses from over-growing. By positively regulating Highwire, NSF2 may be important in keeping synapse growth in check and explains why NMJs with mutant NSF2 have large, disordered morphologies.
Stewart’s group’s most exciting results suggest that when the signaling pathway is turned off, protein filaments that are important for synapse structure cluster much more intensely than synapses that have normal levels of pathway activation. As filament restructuring at the nerve terminal is almost certainly important for the formation of a synapse, Stewart’s group may be on the path to determining how the pathway actually outputs to the formation of a synapse.
