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Michael M Francis PhD

TitleProfessor
InstitutionUMass Chan Medical School
DepartmentNeurobiology
AddressUMass Chan Medical School
364 Plantation Street LRB
Worcester MA 01605
Phone508-856-1496
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    Other Positions
    InstitutionT.H. Chan School of Medicine
    DepartmentNeurobiology

    InstitutionT.H. Chan School of Medicine
    DepartmentNeuroNexus Institute

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentMD/PhD Program

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentNeuroscience

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentPostbaccalaureate Research Education Program


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

    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

    Michael Francis pursued undergradate studies in psychology (psychobiology) at the University of Virginia. He earned his Ph.D. from the Department of Neuroscience at the University of Florida College of Medicine. He pursued postdoctoral training in the Department of Molecular Medicine at Cornell University and the Biology Department at the University of Utah in the lab of Villu Maricq. His predoctoral and postdoctoral studies were supported by NIH NRSA awards. Mike joined the Neurobiology Department at the University of Massachusetts Chan Medical School as a faculty member in 2007.

    Francis Lab Link

     

    Research Interests

    Our laboratory investigates genetic pathways that sculpt the connectivity of circuits, alter their performance, and shape 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 use tools for manipulating or recording neuronal activity 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.
    Newest   |   Oldest   |   Most Cited   |   Most Discussed   |   Timeline   |   Field Summary   |   Plain Text
    PMC Citations indicate the number of times the publication was cited by articles in PubMed Central, and the Altmetric score represents citations in news articles and social media. (Note that publications are often cited in additional ways that are not shown here.) Fields are based on how the National Library of Medicine (NLM) classifies the publication's journal and might not represent the specific topic of the publication. Translation tags are based on the publication type and the MeSH terms NLM assigns to the publication. Some publications (especially newer ones and publications not in PubMed) might not yet be assigned Field or Translation tags.) Click a Field or Translation tag to filter the publications.
    1. Oliver D, Ramachandran S, Philbrook A, Lambert CM, Nguyen KCQ, Hall DH, Francis MM. Correction: Kinesin-3 mediated axonal delivery of presynaptic neurexin stabilizes dendritic spines and postsynaptic components. PLoS Genet. 2022 Jun; 18(6):e1010291. PMID: 35749355.
      Citations:    Fields:    
    2. Oliver D, Ramachandran S, Philbrook A, Lambert CM, Nguyen KCQ, Hall DH, Francis MM. Kinesin-3 mediated axonal delivery of presynaptic neurexin stabilizes dendritic spines and postsynaptic components. PLoS Genet. 2022 01; 18(1):e1010016. PMID: 35089924.
      Citations: 1     Fields:    Translation:AnimalsCells
    3. Ramachandran S, Banerjee N, Bhattacharya R, Lemons ML, Florman J, Lambert CM, Touroutine D, Alexander K, Schoofs L, Alkema MJ, Beets I, Francis MM. A conserved neuropeptide system links head and body motor circuits to enable adaptive behavior. Elife. 2021 11 12; 10. PMID: 34766905.
      Citations: 1     Fields:    Translation:Animals
    4. Oliver D, Norman E, Bates H, Avard R, Rettler M, BĂ©nard CY, Francis MM, Lemons ML. Integrins Have Cell-Type-Specific Roles in the Development of Motor Neuron Connectivity. J Dev Biol. 2019 Aug 27; 7(3). PMID: 31461926.
      Citations:    
    5. Huang YC, Pirri JK, Rayes D, Gao S, Mulcahy B, Grant J, Saheki Y, Francis MM, Zhen M, Alkema MJ. Gain-of-function mutations in the UNC-2/CaV2? channel lead to excitation-dominant synaptic transmission in Caenorhabditis elegans. Elife. 2019 08 05; 8. PMID: 31364988.
      Citations: 8     Fields:    Translation:AnimalsCells
    6. Oliver D, Alexander K, Francis MM. Molecular Mechanisms Directing Spine Outgrowth and Synaptic Partner Selection in Caenorhabditis elegans. J Exp Neurosci. 2018; 12:1179069518816088. PMID: 30546264.
      Citations:    
    7. Philbrook A, Ramachandran S, Lambert CM, Oliver D, Florman J, Alkema MJ, Lemons M, Francis MM. Neurexin directs partner-specific synaptic connectivity in C. elegans. Elife. 2018 07 24; 7. PMID: 30039797.
      Citations: 17     Fields:    Translation:AnimalsCells
    8. 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 05 15; 144(10):1807-1819. PMID: 28420711.
      Citations: 7     Fields:    Translation:AnimalsCells
    9. 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 04; 13(4):e1006697. PMID: 28384151.
      Citations: 10     Fields:    Translation:AnimalsCells
    10. 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.
      Citations: 2     Fields:    Translation:HumansCells
    11. 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.
    12. 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.
      Citations: 13     Fields:    Translation:AnimalsCells
    13. 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.
      Citations:    
    14. 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.
      Citations: 26     Fields:    Translation:AnimalsCells
    15. 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.
      Citations: 19     Fields:    Translation:AnimalsCells
    16. 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 01; 2(3):e25765. PMID: 24778941.
      Citations:    
    17. 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.
      Citations: 58     Fields:    Translation:AnimalsCells
    18. 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.
      Citations: 29     Fields:    Translation:AnimalsCells
    19. 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.
      Citations: 53     Fields:    Translation:AnimalsCells
    20. 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.
      Citations: 23     Fields:    Translation:AnimalsCells
    21. 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.
      Citations: 65     Fields:    Translation:AnimalsCells
    22. 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.
      Citations: 40     Fields:    Translation:AnimalsCells
    23. Emery P, Francis M. Circadian rhythms: timing the sense of smell. Curr Biol. 2008 Jul 08; 18(13):R569-71. PMID: 18606130.
      Citations: 1     Fields:    Translation:AnimalsCells
    24. 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.
      Citations: 38     Fields:    Translation:HumansAnimalsCells
    25. 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.
      Citations: 24     Fields:    Translation:AnimalsCells
    26. 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.
      Citations: 28     Fields:    Translation:AnimalsCells
    27. Francis MM, Maricq AV. Electrophysiological analysis of neuronal and muscle function in C. elegans. Methods Mol Biol. 2006; 351:175-92. PMID: 16988434.
      Citations: 10     Fields:    Translation:Animals
    28. 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.
      Citations: 73     Fields:    Translation:AnimalsCells
    29. 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.
      Citations: 9     Fields:    Translation:AnimalsCells
    30. Webster JC, Francis MM, Porter JK, Robinson G, Stokes C, Horenstein B, Papke RL. Antagonist activities of mecamylamine and nicotine show reciprocal dependence on beta subunit sequence in the second transmembrane domain. Br J Pharmacol. 1999 Jul; 127(6):1337-48. PMID: 10455283.
      Citations: 16     Fields:    Translation:AnimalsCells
    31. Francis MM, Choi KI, Horenstein BA, Papke RL. Sensitivity to voltage-independent inhibition determined by pore-lining region of the acetylcholine receptor. Biophys J. 1998 May; 74(5):2306-17. PMID: 9591658.
      Citations: 7     Fields:    Translation:AnimalsCells
    32. Francis MM, Papke RL. Muscle-type nicotinic acetylcholine receptor delta subunit determines sensitivity to noncompetitive inhibitors, while gamma subunit regulates divalent permeability. Neuropharmacology. 1996; 35(11):1547-56. PMID: 9025102.
      Citations: 11     Fields:    Translation:AnimalsCells
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