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Michael M Francis PhD

TitleAssociate Professor
InstitutionUniversity of Massachusetts Medical School
DepartmentNeurobiology
AddressUniversity of Massachusetts Medical School
364 Plantation Street, LRB
Worcester MA 01605
Phone508-856-1496
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    Other Positions
    InstitutionUMMS - School of Medicine
    DepartmentNeurobiology

    InstitutionUMMS - School of Medicine
    DepartmentNeuroNexus Institute

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentNeuroscience


    Collapse Biography 
    Collapse education and training
    University of Virginia, Charlottesville, VA, United StatesBAPsychology
    University of Florida, Gainesville, FL, United StatesPHD

    Collapse Overview 
    Collapse overview


    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



     



    Research Interests



    Our laboratory investigates mechanisms by which synaptic activity sculpts the connectivity of circuits, alters their performance, and shapes behavior. In particular, we seek to identify regulatory mechanisms that control synaptic activity and understand their contribution to nervous system development, as well as neural circuit output and behavior. To address these questions, we have developed tools for manipulating the activity of specific synapses in a genetically tractable model system, the nematode Caenorhabditis elegans. In addition to an abundance of available genetic tools, C. elegans offers a number of features that make it ideally suited for our work. The pattern of neural connectivity has been established by electron microscopy, allowing for detailed knowledge of synaptic partners in a circuit. The organism is optically transparent, enabling (1) easy imaging of the cellular and subcellular distribution of fluorescent reporters, (2) Ca2+ imaging studies, and (3) optogenetic approaches for cell-specific optical stimulation or inhibition of neurons, all in the intact animal. Finally, we have extensive expertise in patch clamp electrophysiology in order to measure synaptic currents from defined neurons or muscles in vivo.



    Neural circuit development & function



    We are interested in understanding how the complex molecular structure of synapses is achieved and are working to identify molecular pathways that regulate synaptic connectivity. Our studies addressing these questions utilize the experimentally tractable motor circuit of the nematode Caenorhabditis elegans (Fig. 1). In this circuit, a balance of excitatory and inhibitory signaling onto muscles is required to drive sinusoidal movement, and we have found that this is regulated by ionotropic nicotinic acetylcholine receptors (iAChR) bearing strong similarity to mammalian brain iAChRs (Fig. 2). In particular, we have identified an iAChR that is localized at synapses onto GABA neurons and mediates their synaptic excitation. Based on the anatomical connectivity of this circuit (Fig. 1), models of C. elegans locomotion have long assumed that GABA motor neurons respond to cholinergic signals from upstream motor neurons. Our work provides direct molecular support for this AChàGABA neurotransmission model and provides a unique opportunity to investigate conserved mechanisms underlying the formation and functional regulation of neuronal cholinergic synapses. To address these questions, we have developed a system in which we can monitor iAChR localization and trafficking in a single inhibitory neuron dendrite in vivo (Fig. 3)



    Neuromodulation & context-dependent behavior



    We are seeking to understand how neural circuit activity and behavior is shaped through the actions of neuropeptide modulators. To address these questions, we developed a genetic strategy for elevating synaptic excitation of muscles by enhancing the activity of muscle iAChRs, and identified an important role for the cholecystokinin (CCK) homolog nlp-12. We found that deletion of nlp-12/CCK reduced the duration of cholinergic synaptic currents at the NMJ and disrupted local food searching, a behavioral program triggered by reduced food availability (Fig. 4). While CCK function is associated with satiety signaling in mammals, the neural circuit basis for this remains unclear. We found that behavioral responses to reduced food availability are shaped through context-dependent NLP-12/CCK modulation of motor circuit responsiveness to sensory information about food (Fig. 4), a striking example of how the approaches we are pursuing enable us to gain novel insights into signaling pathways directly relevant to mammalian neurobiology. In related studies, we are investigating context-dependent neuropeptide modulation in other behavioral paradigms, such as egg-laying.



    Ion channel-mediated neurodegeneration



    Roles for ionotropic receptor mediated signaling in the nervous system extend far beyond a well-characterized participation in cell-cell communication at synapses.  Ionotropic receptor activation is one of several key factors that influences cell survival in developing and mature nervous systems. We have found that that hyperactivation of iAChRs located on excitatory motor neurons leads to motor neuron degeneration. Interestingly, under conditions in which death of the cell bodies was attenuated, we noted iAChR hyperactivation led to progressive destabilization of the motor neuron processes and, ultimately, paralysis in these animals. Our work to date suggests that ion channel hyperactivation has distinct consequences for the cell soma compared with neurites. We are now working to uncover the molecular pathways that underlie ion channel mediated toxicity in neuronal cell bodies as well as processes.



     





    Fig. 1. Adult C. elegans motor circuit. For clarity, only ventral ACh to dorsal GABA is shown. ACh motor neurons (MNs, gray) make synaptic connections with ventral muscle cells (brown) and dorsally projecting GABA MNs (purple).





    Fig 2. Two iAChR classes control motor neuron excitation. ACh motor neurons (gray) form dyadic synapses onto muscles (tan) and GABA motor neurons (purple).Distinct iAChR populations (ACR-2/12ACh and ACR-12GABA) regulate motor neuron activity. ACR-2/12ACh receptors are diffusely localized along dendrites of ACh motor neurons and play a primarily modulatory role. ACR-12GABA receptors form a punctate pattern along the dendrites of GABA motor neurons and mediate synaptic activation of GABA motor neurons.





    Fig 3. ACR-12 iAChR localization in the GABA motor neuron, DD1.





    Fig 4. Context-dependent dopamine regulation of NLP-12 release from the interneuron DVA modulates food seeking behavior.



    Collapse 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.



    Collapse Post Docs

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




    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    List All   |   Timeline
    1. Barbagallo B, Philbrook A, Touroutine D, Banerjee N, Oliver D, Lambert CM, Francis MM. Excitatory neurons sculpt GABAergic neuronal connectivity in the C. elegans motor circuit. Development. 2017 Apr 18. PMID: 28420711.
      View in: PubMed
    2. Banerjee N, Bhattacharya R, Gorczyca M, Collins KM, Francis MM. Local neuropeptide signaling modulates serotonergic transmission to shape the temporal organization of C. elegans egg-laying behavior. PLoS Genet. 2017 Apr 06; 13(4):e1006697. PMID: 28384151.
      View in: PubMed
    3. Francis MM, Freeman MR. Dendrites actively restrain axon outgrowth and regeneration. Proc Natl Acad Sci U S A. 2016 May 17; 113(20):5465-6. PMID: 27147603.
      View in: PubMed
    4. Philbrook A and Francis MM. Nicotinic Acetylcholine Receptor Technologies, edited by Ming D. Li. Emerging Technologies in the analysis of C. elegans Nicotinic Acetylcholine Receptors. 2016; 77-96.
    5. He S, Philbrook A, McWhirter R, Gabel CV, Taub DG, Carter MH, Hanna IM, Francis MM, Miller DM. Transcriptional Control of Synaptic Remodeling through Regulated Expression of an Immunoglobulin Superfamily Protein. Curr Biol. 2015 Oct 05; 25(19):2541-8. PMID: 26387713.
      View in: PubMed
    6. Bhattacharya R, Francis MM. In the proper context: Neuropeptide regulation of behavioral transitions during food searching. Worm. 2015 Jul-Sep; 4(3):e1062971. PMID: 26430569.
      View in: PubMed
    7. Bhattacharya R, Touroutine D, Barbagallo B, Climer J, Lambert CM, Clark CM, Alkema MJ, Francis MM. A conserved dopamine-cholecystokinin signaling pathway shapes context-dependent Caenorhabditis elegans behavior. PLoS Genet. 2014 Aug; 10(8):e1004584. PMID: 25167143.
      View in: PubMed
    8. Kowalski JR, Dube H, Touroutine D, Rush KM, Goodwin PR, Carozza M, Didier Z, Francis MM, Juo P. The Anaphase-Promoting Complex (APC) ubiquitin ligase regulates GABA transmission at the C. elegans neuromuscular junction. Mol Cell Neurosci. 2014 Jan; 58:62-75. PMID: 24321454.
      View in: PubMed
    9. Philbrook A, Barbagallo B, Francis MM. A tale of two receptors: Dual roles for ionotropic acetylcholine receptors in regulating motor neuron excitation and inhibition. Worm. 2013 Jul 1; 2(3):e25765. PMID: 24778941.
      View in: PubMed
    10. 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; 11(4):e1001529. PMID: 23565061.
      View in: PubMed
    11. 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. PMID: 23536067.
      View in: PubMed
    12. 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. PMID: 22464329.
      View in: PubMed
    13. 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. PMID: 20962215.
      View in: PubMed
    14. 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. PMID: 19477154.
      View in: PubMed
    15. 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. PMID: 18817737.
      View in: PubMed
    16. Emery P, Francis M. Circadian rhythms: timing the sense of smell. Curr Biol. 2008 Jul 8; 18(13):R569-71. PMID: 18606130.
      View in: PubMed
    17. 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. PMID: 16818877.
      View in: PubMed
    18. 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. PMID: 16818875.
      View in: PubMed
    19. 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. PMID: 16418277.
      View in: PubMed
    20. Francis MM, Maricq AV. Electrophysiological analysis of neuronal and muscle function in C. elegans. Methods Mol Biol. 2006; 351:175-92. PMID: 16988434.
      View in: PubMed
    21. 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. PMID: 15944127.
      View in: PubMed
    22. 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. PMID: 15761116.
      View in: PubMed
    23. 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. PMID: 12536132.
      View in: PubMed
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