F A C U L T Y P R O F I L E
MC CABE, BRIAN D. , Ph.D.
Molecular genetics of synapse development and plasticity.
Office: Physicians & Surgeons | 11th floor | Room 420
McCabe Lab Website
Perception, learning, memory and behavior are thought to be possible through the plastic ability of synaptic connections to alter their function, shape and complexity in response to changes in development, activity or experience. We are interested in defining the molecular pathways that regulate synaptic structural growth and change, understanding how activity and experience influence these pathways, and characterizing the molecular building blocks produced or altered when synapses rearrange. To address these problems, we use an unbiased forward genetic approach in the fruit fly Drosophila melanogaster. Drosophila has proven itself 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, allowing genomic information to be combined with powerful genetic, molecular, biochemical and cell biology tools.
One of our primary focuses is the neuromuscular junction (NMJ) synapse of Drosophila, which we use as a model system for synaptic plasticity. Each NMJ synapse is uniquely identifiable allowing single cell experimental resolution in vivo and has been extensively characterized at the cellular, ultrastructural and electrophysiological levels. During their lifecycle Drosophila larval muscles grow at an extraordinary rate, accompanied by a concomitant increase in both the size, complexity and neurotransmitter output of neuromuscular synapses. This dynamic morphological growth makes the NMJ an ideal synapse to study plastic changes during development. Furthermore, altering motor activity can influence the growth and function of these synapses allowing experience 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 observed in live animals through the transparent cuticle without dissection. We have taken advantage of these markers to carry out large scale screens for mutants with aberrant synaptic development.
Current projects in the lab include: defining how retrograde trophic factors (in particular BMP signaling) regulate synaptic growth, characterizing novel mutants that disrupt many aspects of synapse plasticity, elucidating the role of molecules implicated in synaptic function from gene expression analysis and developing new models for human neuromuscular disease.
Liebl, F.L.W, Werner, K.M., Sheng, Q., McCabe, B.D., and Featherstone, D.E. 2006. A Genome-wide P-Element Screen for Drosophila Synaptogenesis Mutants. J. Neurobiology 66:332-347
Penney, E.B., and McCabe, B.D. 2005. All neuropathies great and small. Journal of Clinical Investigation 115:3026-3034
McCabe, B. D., Hom, S., Aberle, H., Fetter, R. D., Marques, G., Haerry, T. E., O'Connor, M. B., Goodman, C. S. and Haghighi, A. P. 2004. Highwire regulates presynaptic BMP signaling essential for synaptic growth. Neuron 41, 891-905.
McCabe, B. D., Marques, G., Haghighi, A. P., Fetter, R. D., Crotty, L. M., Haerry, T. E., Goodman, C. S., and O'Connor, M. B. 2003. The BMP homolog Gbb provides a retrograde signal that regulates synapse growth at the Drosophila neuromuscular junction. Neuron 39, 241-254.