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| RESEARCH THEME:
Molecular genetics of neuromuscular synapse development and plasticity.
The synaptic connections between motor neurons and muscles, known as neuromuscular junctions, allow thought to be transformed into expression by commuting neuronal impulses into muscle movement. Neuromuscular junctions (NMJ) are not static structures, but can change in size, shape and functional properties during development, in reaction to altered motor activity or in response to injury and disease. Research in my laboratory aims to determine the molecular pathways that regulate NMJ growth and change, understand how motor activity influences NMJ attributes, and to characterize the protein building blocks required to assemble neuromuscular synapses. To address these questions, we employ the powerful genetic tools of the fruit fly Drosophila melanogaster as a model system. Drosophila has proven to be an invaluable model organism because, in addition to having extensive genetic conservation to humans, it also shares many of the same morphological, physiological and behavioral complexities. The Drosophila genome is completely sequenced and annotated, allowing genomic information to be combined with unrivaled genetic, molecular, biochemical and cell biology tools. Each NMJ synapse in Drosophila is uniquely identifiable allowing single cell experimental resolution in vivo and Drosophila NMJ synapses have been extensively characterized at the cellular, ultrastructural and electrophysiological levels. During their short lifecycle, Drosophila larval muscles grow at an extraordinary rate, inducing a concomitant increase in the size, complexity and neurotransmitter output of neuromuscular synapses. This dynamic morphological growth makes the Drosophila NMJ an ideal synapse to study morphological change during development. Furthermore, altering motor output can influence the growth and function of these synapses allowing activity-dependent aspects of synaptic plasticity to be studied. Using transgenic fluorescent protein markers that label both the pre- and post-synapse, synaptic development can be easily observed in live animals through the transparent cuticle. We have taken advantage of these tools to carry out large scale screens for genetic mutants with aberrant synaptic development. We have found that a large and diverse number of proteins are required for normal NMJ development. For example, we discovered that muscles provide retrograde trophic signals, including by members of the TGF-b family of cytokines, that are essential for neuromuscular junction growth. We are continuing to characterize new mutants that disrupt many aspects of NMJ formation, assembly or development which we have identified in our screens. Furthermore, many genes disrupted in human motor neuron diseases such ALS and SMA have closely related homologs in Drosophila. We are exploiting this conservation to apply the high-throughput genetic tools of this tractable model system to yield greater insights into the molecular basis of these diseases. BACKGROUND AND EDUCATION : Brian McCabe is Assistant Professor of Physiology and Cellular Biophysics. He is also faculty in the Center for Neurobiology and Behavior. He received his Ph.D. from the University of Cambridge, England. His postdoctoral research was carried out in the University of California at Berkeley in the laboratory of Corey Goodman. He became an Assistant Professor of Physiology and Cellular Biophysics in 2004. EDUCATION AND TRAINING:
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