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    Michael M Francis PhD

    TitleAssistant Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentNeurobiology
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB
    Worcester MA 01605
    Phone508-856-1496
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentNeuroscience

        Overview 
        Narrative
        Contact Information:
        Michael M. Francis, Ph.D.
        University of Massachusetts Medical School
        Department of Neurobiology, 715 Lazare Research Building
        364 Plantation Street
        Worcester, MA 01605 USA
        phone: 508-856-1496 (office)
        phone: 508-856-1609 (lab)

        Biography

        Mike 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.

        Francis Lab Link

        Mike

        Synaptic transmission and C. eleganslocomotion

        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 Junction

        At least 3 distinct subtypes of post-synaptic receptors are expressed in C. elegansbody 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 Excitability

        In 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.

        Mike's Image 1

        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.

        Mike's Figure 2



        Rotation Projects

        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.



        Post Docs

        A postdoctoral position is available to study in this laboratory. Contact Dr.Francis for additional details.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Donnelly JL, Clark CM, Leifer AM, Pirri JK, Haburcak M, Francis MM, Samuel AD, Alkema MJ. Monoaminergic Orchestration of Motor Programs in a Complex C. elegans Behavior. PLoS Biol. 2013 Apr; 11(4):e1001529.
          View in: PubMed
        2. Petrash HA, Philbrook A, Haburcak M, Barbagallo B, Francis MM. ACR-12 Ionotropic Acetylcholine Receptor Complexes Regulate Inhibitory Motor Neuron Activity in Caenorhabditis elegans. J Neurosci. 2013 Mar 27; 33(13):5524-32.
          View in: PubMed
        3. Jensen M, Hoerndli FJ, Brockie PJ, Wang R, Johnson E, Maxfield D, Francis MM, Madsen DM, Maricq AV. Wnt signaling regulates acetylcholine receptor translocation and synaptic plasticity in the adult nervous system. Cell. 2012 Mar 30; 149(1):173-87.
          View in: PubMed
        4. Barbagallo B, Prescott HA, Boyle P, Climer J, Francis MM. A dominant mutation in a neuronal acetylcholine receptor subunit leads to motor neuron degeneration in Caenorhabditis elegans. J Neurosci. 2010 Oct 20; 30(42):13932-42.
          View in: PubMed
        5. Pirri JK, McPherson AD, Donnelly JL, Francis MM, Alkema MJ. A tyramine-gated chloride channel coordinates distinct motor programs of a Caenorhabditis elegans escape response. Neuron. 2009 May 28; 62(4):526-38.
          View in: PubMed
        6. Wang R, Walker CS, Brockie PJ, Francis MM, Mellem JE, Madsen DM, Maricq AV. Evolutionary conserved role for TARPs in the gating of glutamate receptors and tuning of synaptic function. Neuron. 2008 Sep 25; 59(6):997-1008.
          View in: PubMed
        7. Emery P, Francis M. Circadian rhythms: timing the sense of smell. Curr Biol. 2008 Jul 8; 18(13):R569-71.
          View in: PubMed
        8. Walker CS, Brockie PJ, Madsen DM, Francis MM, Zheng Y, Koduri S, Mellem JE, Strutz-Seebohm N, Maricq AV. Reconstitution of invertebrate glutamate receptor function depends on stargazin-like proteins. Proc Natl Acad Sci U S A. 2006 Jul 11; 103(28):10781-6.
          View in: PubMed
        9. Walker CS, Francis MM, Brockie PJ, Madsen DM, Zheng Y, Maricq AV. Conserved SOL-1 proteins regulate ionotropic glutamate receptor desensitization. Proc Natl Acad Sci U S A. 2006 Jul 11; 103(28):10787-92.
          View in: PubMed
        10. Zheng Y, Brockie PJ, Mellem JE, Madsen DM, Walker CS, Francis MM, Maricq AV. SOL-1 is an auxiliary subunit that modulates the gating of GLR-1 glutamate receptors in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2006 Jan 24; 103(4):1100-5.
          View in: PubMed
        11. Francis MM, Maricq AV. Electrophysiological analysis of neuronal and muscle function in C. elegans. Methods Mol Biol. 2006; 351:175-92.
          View in: PubMed
        12. Francis MM, Evans SP, Jensen M, Madsen DM, Mancuso J, Norman KR, Maricq AV. The Ror receptor tyrosine kinase CAM-1 is required for ACR-16-mediated synaptic transmission at the C. elegans neuromuscular junction. Neuron. 2005 May 19; 46(4):581-94.
          View in: PubMed
        13. Papke RL, Buhr JD, Francis MM, Choi KI, Thinschmidt JS, Horenstein NA. The effects of subunit composition on the inhibition of nicotinic receptors by the amphipathic blocker 2,2,6,6-tetramethylpiperidin-4-yl heptanoate. Mol Pharmacol. 2005 Jun; 67(6):1977-90.
          View in: PubMed
        14. Francis MM, Mellem JE, Maricq AV. Bridging the gap between genes and behavior: recent advances in the electrophysiological analysis of neural function in Caenorhabditis elegans. Trends Neurosci. 2003 Feb; 26(2):90-9.
          View in: PubMed
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