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Michael Francis, Ph.D.Academic Role: Assistant Professor
Faculty Appointment(s) In:
Joint Faculty In:
Synaptic transmission and C. elegans locomotion Fast synaptic transmission underlies the vast majority of cell-cell signaling in the nervous system. Alterations in synaptic properties can have profound effects on the output of a neural circuit. What genes regulate synaptic properties and how do changes in circuit properties translate into changes in behavior? Research in my laboratory explores these general questions in the context of a neural circuit responsible for locomotory behavior in the model organism Caenorhabditis elegans. C. elegans is a free-living soil nematode that possesses a simple, well-defined nervous system and is amenable to rapid genetic analysis. Our research pairs genetic and cell biological analyses with recently developed patch-clamp electrophysiological techniques to study the molecular and cellular basis of C. elegans movement. The neurons responsible for controlling C. elegans movement are well characterized and the basic locomotory control circuit consists of 3 synapses (Figure 1). Signaling between neurons of this circuit is mediated by a variety of conserved synaptic proteins, including ligand-gated ion channels such as glutamate receptors and nicotinic acetylcholine receptors. Our work focuses on the following areas: Synapses at the Neuromuscular JunctionAt least 3 distinct subtypes of post-synaptic receptors are expressed in C. elegans body wall muscle: a single subtype of GABA receptor and at least 2 subtypes of ionotropic acetylcholine receptor (AChR). The 2 AChR subtypes present at the neuromuscular junction (NMJ) can be distinguished pharmacologically on the basis of their differential sensitivity to the cholinergic agonists levamisole and nicotine. Recently, we identified the acr-16 gene as encoding an essential component of nicotine-sensitive receptors. Worms lacking both levamisole receptors and ACR-16 receptors are paralyzed and exhibit a complete loss of excitatory synaptic transmission at the NMJ (Figure 2). We have found that the Ror receptor tyrosine kinase CAM-1 is selectively required for normal ACR-16 mediated synaptic currents. We are continuing to study the role of CAM-1 as well as conducting forward genetic screens to identify additional modifiers of cholinergic signaling at the NMJ. These modifiers may include gene products required for trafficking, localization or function of post-synaptic receptors as well as genes required for neurotransmitter release and we are currently employing a multi-faceted approach including cell biology, microscopy, electrophysiology and genetics to determine the precise functional roles of these modifiers. We believe that our approach will allow us to identify conserved gene products that regulate cholinergic neurotransmission in C. elegans as well as in the vertebrate nervous system. Motor Neuron ExcitabilityIn addition to the nAChRs present at the NMJ, a wide variety of nAChR subtypes are also expressed in the nervous system, in particular in motor neurons. However, little is known about the role of these receptors in regulating motor neuron excitability and how excitation of the motor neurons couples to muscle contraction and ultimately movement. We have identified several additional acr gene products that are expressed in motor neurons and are currently exploring the role of these AChRs in regulating locomotion. We are also taking a forward genetic approach to identify modifiers of synaptic transmission in motor neurons. The identification of new genes that regulate motor neuron synapses will help provide a more clear mechanistic understanding of synaptic development, post-synaptic receptor localization, ion channel function and the role these receptors play in controlling C. elegans movement. Figure 1. Schematic of the simplified C. elegans locomotory circuit. Stimuli such as light touch to the tip of the nose initiate an avoidance response in C. elegans. Sensory neurons make synaptic contacts onto forward/backward command interneurons that make synaptic contacts onto A and B motor neurons, initiating either forward or backward movement.
Figure 2. Whole-cell patch clamp current recordings from C. elegans body wall muscle. Current responses to application of acetylcholine in wild-type worms include 2 components that can be separated pharmacologically using the selective drugs levamisole and nicotine. unc-29 mutants lack current responses to levamisole while acr-16 mutants lack current responses to nicotine. unc-29;acr-16 double mutants show a complete lack of excitatory current in body wall muscle.
Representative PublicationsEmery P, Francis M. Circadian rhythms: timing the sense of smell. (2008) Current Biology 18(13): R569-71. Walker CS, Brockie PJ, Madsen DM, Francis MM, Zheng Y, Koduri S, Mellem JE, Strutz-Seebohm N, Maricq AV.(2006) Reconstitution of invertebrate glutamate receptor function depends on stargazin-like proteins. Proc Natl Acad Sci U S A. 103(28):10781-6. Walker CS*, Francis MM*, Brockie PJ, Madsen DM, Zheng Y, Maricq AV.(2006) Conserved SOL-1 proteins regulate ionotropic glutamate receptor desensitization. Proc Natl Acad Sci USA 103(28):10787-92. *these authors contributed equally Francis MM, Maricq, AV. (2006) Electrophysiological analysis of neuronal and muscle function in C. elegans. Methods Mol Biol. 351: 175-92. Zheng Y., P.J. Brockie, J.E. Mellem, D.M. Madsen, C.S. Walker, M.M. Francis and A.V. Maricq. (2006) SOL-1 is an auxiliary subunit that modulates the gating of GLR-1 glutamate receptors in C. elegans. Proc Natl Acad Sci USA 103(4): 1100-5. Francis M.M., S.P. Evans, M. Jensen, D.M. Madsen, K.R. Norman, J. Mancuso, and A.V. Maricq. (2005) The Ror Receptor Tyrosine Kinase CAM-1 is Required for ACR-16 Mediated Synaptic Transmission at the C. elegans Neuromuscular Junction. Neuron 46(4): 581-594. Francis, M.M, J.E. Mellem and A.V. Maricq. (2003) Bridging the gap between genes and behavior: recent advances in the electrophysiological analysis of neural function in Caenorhabditis elegans. Trends in Neurosciences, 26(2):90-99.
Potential Rotation Projects The Francis lab studies the regulation of post-synaptic neurotransmitter receptors and how alterations in synaptic transmission lead to changes in behavior. We combine patch-clamp electrophysiology with the powerful genetic techniques available in C. elegans. A variety of potential rotation projects centered around the exploration of synaptic function, mechanisms for receptor localization and analysis of C. elegans movement are available. Students can expect to have access to training in a broad range of techniques including forward and reverse genetic strategies, molecular biology, fluorescent microscopy and electrophysiology. As projects are always evolving, I encourage students to contact the lab directly to discuss your specific interests.
BiographyMike Francis received his B.A. (1992) in psychobiology from the University of Virginia. He received a predoctoral National Research Service Award from NIMH to pursue his Ph.D. (1998) in the Department of Neuroscience at the University of Florida. He received a postdoctoral National Research Service Award from NIDA to pursue postdoctoral training in the Department of Molecular Medicine at Cornell University. He pursued additional postdoctoral training at the University of Utah and joined the faculty at the University of Utah as a Research Assistant Professor in 2001. Mike joined the faculty of University of Massachusetts Medical School in January 2007.
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Lazare Research Bldg., 364 Plantation Street Worcester, MA 01605-2324