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    Marc R Freeman PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentNeurobiology
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB-703
    Worcester MA 01605
    Phone508-856-6136
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentNeuroscience

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentTranslational Science

        Overview 
        Narrative

        Biography

        Marc Freeman earned his B.S. in Biology from Eastern Connecticut State University in 1993. He carried out his doctoral training in the laboratory of John Carlson at Yale University where he studied Drosophila olfaction, obtained his PhD in Biology in 1999. Freeman trained as a postdoctoral associate with Chris Q Doe at the University of Oregon from 1999-2004, studying Drosophila embryonic neurogenesis, with a particular focus on glial cell development. He started his laboratory in the Department of Neurobiology at The University of Massachusetts Medical School in 2004 which focuses on glia-neuron interactions. Freeman was selected as a Smith Family New Investigator (2004), an Alfred P Sloan Research Fellow (2005), a Howard Hughes Medical Institute Early Career Scientist (2009), and appointed an Investigator of the Howard Hughes Medical Institute (2013).

         

         

        Molecular basis of neuron-glia signalingMarc

        Neurons are not alone in the nervous system. Glial cells constitute the majority of the cells in human brain and are emerging as major regulators of nervous system development, function, and health. Despite their abundance in the nervous system we know surprisingly little about any aspect of glial biology. How are glia made? How diverse are they at the molecular level? How do they take on their elaborate morphologies during development? How do they interact with neurons during neural circuit assembly or plasticity? What is their function in the mature brain?

        We have been pioneering the use of Drosophila as a model system to pry deeply into the biology of this amazing cell type. Our current major lines of investigation include defining: (1) genetic programs that promote the development and function of specific glial subtypes, especially astrocytes, (2) neuron-glia signaling events that sculpt neural circuit assembly and plasticity, (3) glial responses to brain injury or disease, and (4) molecular pathways driving axon auto-destruction.

        1) Development and function of astrocytes

        Shortly afterthey are born mammalian astrocytes invade synapse rich regions of the brain, and become intimately associated with nearly all synapses, the fundamental unit of neuron-neuron signaling. Why are astrocytes so closely coupled with synapses? Exciting recent work points to important roles for astrocytes in synapse formation, maturation, and efficacy, and it is quite likely that glia are also active participants in synaptic signaling and plasticity. We wish to understand the molecular bases of these interactions and the precise roles of glia in CNS information processing.

        Are there astrocytes in Drosophila? Using a variety of molecular-genetic approaches we have recently identified a cell type in the Drosophila brain that bears a striking resemblance to mammalian astrocytes at the morphological and molecular levels. For example, the fly astrocyte takes on a tortuous morphology, extending profuse membrane specializations throughout the brain which associate closely with CNS synapses. These cells, like mammalian astrocytes, expresses transporters essential for the clearance of major neurotransmitters from the synaptic cleft (e.g. glutamate and GABA), arguing for an important role for fly astrocytes in modulating neurotransmitter tone in the brain. Using our collection of newly-developed tools we have embarked on the first molecular-genetic analysis of astrocyte development and function in an organism amenable to rapid genetic analysis. Major question we are exploring include: How do astrocytes take on their tortuous morphologies? Do astrocytes occupy unique spatial domains in the CNS? Is astrocyte morphology or synapse association responsive to neural activity? Are astrocytes actively remodeled during development? How do astrocytes modulate synaptic signaling?

        2) Neuron-glia signaling sculpts axonal and synaptic connectivity

        It is widely believed that glial cells play an important role in wiring the nervous system, but compelling evidence supporting a requirement for glia in the establishment of neural connectivity has remained scarce. We are exploring the mechanisms by which glia sculpt neural connectivity during development in two contexts: (1) the adult Drosophila antennal lobe, and (2) the larval neuromuscular junction (NMJ). Through glial-specific knockdown of a number of signaling molecules we have found that developing adult brain glia are critical players in the wiring of the adult olfactory system. This exciting observation implicates glia in establishment of the precise spatial map of ORN axon connectivity in the antennal lobe. We are now seeking to identify how neuron-glia interactions sculpt axonal connections in this tissue. To explore how glia sculpt synaptic fields we turned to the Drosophila larval NMJ (in collaboration with Vivian Budnik). During larval life the NMJ increase ~100-fold in size, and thereby acts as a developmental model for synaptic plasticity. Interestingly, we find that suppressing glial phagocytic activity leads to the accumulation of massive amounts of presynaptically-derived debris at the NMJ and a dramatic decrease in the formation of new boutons. We currently believe that normal synapse expansion entails large-scale shedding of presynaptic membranes, that glia transient invade the NMJ to engulf this material, and that constitutive clearance presynaptic material is essential for normal synaptic expansion. We further hope to use the Drosophila NMJ to probe fundamental questions in glial biology by: (1) developing it as a model for a "tripartite synapse" where the effects of glial cells on synaptic physiology can be determined; (2) exploring in live preparations the effects of neural activity on glial motility and Ca2+ signaling; and (3) determining additional ways in which glia can modulate synaptic connectivity.

        3) Molecular pathways mediating glial immune function

        Glial have the impressive ability to sense any neural injury (e.g. spinal cord injury, ischemia, or neurodegenerative disease) and respond by undergoing “reactive gliosis”, a process whereby glia exhibit dramatic changes in morphology and gene expression patterns, migrate to the injury site, and manage brain responses to trauma. Reactive gliosis has been a major topic of study in the field of glial cell biology for over a decade, but molecular pathways mediating neuron-glia signaling after injury have remained largely undefined. We have recently developed a simple assay for acute nerve injury in Drosophila, and showed that severed Drosophila axons degenerate after a defined latent phase, and elicit potent morphological and molecular responses by glia: within hours after injury glia upregulated the expression of Draper (the Drosophila ortholog of the C. elegans cell corpse engulfment receptor CED-1), extended membranes toward severed axons, and phagocytosed degenerating axonal debris. In draper mutants glia failed to respond to axon injury or clear axonal debris from the CNS. These exciting observations demonstrated that Drosophila glia can respond to brain trauma and phagocytose degenerating axonal debris, and identify Draper as a central mediator of these events. In addition, based on the requirement for the cell corpse engulfment receptor Draper for clearance, this work suggests for the first time that cell corpses and degenerating axons may present similar engulfment cues to local phagocytes. We are now further defining the Draper signaling pathway and are identifying additional signaling molecules that mediate the neuronà glia signaling events after axon injury.

        4) Molecular mechanisms of axon auto-destruction

        We are very interested in understanding how axons undergo auto-destruction and autonomously tag themselves for engulfment by glia. For over a century severed axons were thought to passively waste away due to a lack of nutrients from the cell body. However the identification of the slow Wallerian degeneration (Wlds) molecule, which can suppress axon degeneration in mice for weeks after axotomy, forced us to reconsider this notion. It is now thought that Wallerian degeneration may be an active program of axon auto-destruction, akin to apoptotic death, that is somehow suppressed by Wlds. We recently made the exciting discovery that severed Drosophila undergo Wallerian degeneration that can be strongly suppressed by mouse Wlds, thus the molecular mechanisms driving Wallerian degeneration and Wlds function are conserved in Drosophila and mammals. In addition, we found that severed Wlds-expressing axons do not elicit any response from glia, indicating that axonal production of the neuronà glia injury signal that activates glial phagocytosis is genetically downstream of Wlds. This work opens the door to a genetic analysis of axon auto-destruction pathways and we have recently used this approach to identify one of the first "axon death" genes, dSarm/Sarm1. We are now deeply immersed in trying to understand (1) the signaling pathways that actively drive axon auto-destruction, including dSarm/Sarm1; (2) how Wlds protects severed axons from auto-destruction; and (3) the molecular identity of axonal injury signals.

         



        Bibliographic 
        selected publications
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        1. Stork T, Sheehan A, Tasdemir-Yilmaz OE, Freeman MR. Neuron-Glia Interactions through the Heartless FGF Receptor Signaling Pathway Mediate Morphogenesis of Drosophila Astrocytes. Neuron. 2014 Jul 16; 83(2):388-403.
          View in: PubMed
        2. Neukomm LJ, Burdett TC, Gonzalez MA, Züchner S, Freeman MR. Rapid in vivo forward genetic approach for identifying axon death genes in Drosophila. Proc Natl Acad Sci U S A. 2014 Jul 8; 111(27):9965-70.
          View in: PubMed
        3. Kerr KS, Fuentes-Medel Y, Brewer C, Barria R, Ashley J, Abruzzi KC, Sheehan A, Tasdemir-Yilmaz OE, Freeman MR, Budnik V. Glial wingless/wnt regulates glutamate receptor clustering and synaptic physiology at the Drosophila neuromuscular junction. J Neurosci. 2014 Feb 19; 34(8):2910-20.
          View in: PubMed
        4. Rooney TM, Freeman MR. Drosophila models of neuronal injury. ILAR J. 2014 Jan; 54(3):291-5.
          View in: PubMed
        5. Tasdemir-Yilmaz OE, Freeman MR. Astrocytes engage unique molecular programs to engulf pruned neuronal debris from distinct subsets of neurons. Genes Dev. 2014 Jan 1; 28(1):20-33.
          View in: PubMed
        6. Corty MM, Freeman MR. Cell biology in neuroscience: Architects in neural circuit design: Glia control neuron numbers and connectivity. J Cell Biol. 2013 Nov 11; 203(3):395-405.
          View in: PubMed
        7. Freeman MR, Rowitch DH. Evolving concepts of gliogenesis: a look way back and ahead to the next 25 years. Neuron. 2013 Oct 30; 80(3):613-23.
          View in: PubMed
        8. Coutinho-Budd J, Freeman MR. Probing the enigma: unraveling glial cell biology in invertebrates. Curr Opin Neurobiol. 2013 Dec; 23(6):1073-9.
          View in: PubMed
        9. Milde S, Fox AN, Freeman MR, Coleman MP. Deletions within its subcellular targeting domain enhance the axon protective capacity of Nmnat2 in vivo. Sci Rep. 2013; 3:2567.
          View in: PubMed
        10. Wishart TM, Rooney TM, Lamont DJ, Wright AK, Morton AJ, Jackson M, Freeman MR, Gillingwater TH. Combining comparative proteomics and molecular genetics uncovers regulators of synaptic and axonal stability and degeneration in vivo. PLoS Genet. 2012; 8(8):e1002936.
          View in: PubMed
        11. Ziegenfuss JS, Doherty J, Freeman MR. Distinct molecular pathways mediate glial activation and engulfment of axonal debris after axotomy. Nat Neurosci. 2012 Jul; 15(7):979-87.
          View in: PubMed
        12. Osterloh JM, Yang J, Rooney TM, Fox AN, Adalbert R, Powell EH, Sheehan AE, Avery MA, Hackett R, Logan MA, MacDonald JM, Ziegenfuss JS, Milde S, Hou YJ, Nathan C, Ding A, Brown RH, Conforti L, Coleman M, Tessier-Lavigne M, Züchner S, Freeman MR. dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science. 2012 Jul 27; 337(6093):481-4.
          View in: PubMed
        13. Logan MA, Hackett R, Doherty J, Sheehan A, Speese SD, Freeman MR. Negative regulation of glial engulfment activity by Draper terminates glial responses to axon injury. Nat Neurosci. 2012 May; 15(5):722-30.
          View in: PubMed
        14. Avery MA, Rooney TM, Pandya JD, Wishart TM, Gillingwater TH, Geddes JW, Sullivan PG, Freeman MR. WldS prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca2+ buffering. Curr Biol. 2012 Apr 10; 22(7):596-600.
          View in: PubMed
        15. Stork T, Bernardos R, Freeman MR. Analysis of glial cell development and function in Drosophila. Cold Spring Harb Protoc. 2012 Jan; 2012(1):1-17.
          View in: PubMed
        16. Freeman MR. Specification and morphogenesis of astrocytes. Science. 2010 Nov 5; 330(6005):774-8.
          View in: PubMed
        17. McPhee CK, Logan MA, Freeman MR, Baehrecke EH. Activation of autophagy during cell death requires the engulfment receptor Draper. Nature. 2010 Jun 24; 465(7301):1093-6.
          View in: PubMed
        18. Coleman MP, Freeman MR. Wallerian degeneration, wld(s), and nmnat. Annu Rev Neurosci. 2010; 33:245-67.
          View in: PubMed
        19. Osterloh JM, Freeman MR. Neuronal death or dismemberment mediated by Sox14. Nat Neurosci. 2009 Dec; 12(12):1479-80.
          View in: PubMed
        20. Fuentes-Medel Y, Logan MA, Ashley J, Ataman B, Budnik V, Freeman MR. Glia and muscle sculpt neuromuscular arbors by engulfing destabilized synaptic boutons and shed presynaptic debris. PLoS Biol. 2009 Aug; 7(8):e1000184.
          View in: PubMed
        21. Doherty J, Logan MA, Tasdemir OE, Freeman MR. Ensheathing glia function as phagocytes in the adult Drosophila brain. J Neurosci. 2009 Apr 15; 29(15):4768-81.
          View in: PubMed
        22. Avery MA, Sheehan AE, Kerr KS, Wang J, Freeman MR. Wld S requires Nmnat1 enzymatic activity and N16-VCP interactions to suppress Wallerian degeneration. J Cell Biol. 2009 Feb 23; 184(4):501-13.
          View in: PubMed
        23. Ziegenfuss JS, Biswas R, Avery MA, Hong K, Sheehan AE, Yeung YG, Stanley ER, Freeman MR. Draper-dependent glial phagocytic activity is mediated by Src and Syk family kinase signalling. Nature. 2008 Jun 12; 453(7197):935-9.
          View in: PubMed
        24. Emery P, Freeman MR. Glia got rhythm. Neuron. 2007 Aug 2; 55(3):337-9.
          View in: PubMed
        25. Logan MA, Freeman MR. The scoop on the fly brain: glial engulfment functions in Drosophila. Neuron Glia Biol. 2007 Feb; 3(1):63-74.
          View in: PubMed
        26. Freeman MR. A look inside. Neuron Glia Biol. 2007 Feb; 3(1):1-3.
          View in: PubMed
        27. MacDonald JM, Beach MG, Porpiglia E, Sheehan AE, Watts RJ, Freeman MR. The Drosophila cell corpse engulfment receptor Draper mediates glial clearance of severed axons. Neuron. 2006 Jun 15; 50(6):869-81.
          View in: PubMed
        28. Freeman MR, Doherty J. Glial cell biology in Drosophila and vertebrates. Trends Neurosci. 2006 Feb; 29(2):82-90.
          View in: PubMed
        29. Freeman MR. Sculpting the nervous system: glial control of neuronal development. Curr Opin Neurobiol. 2006 Feb; 16(1):119-25.
          View in: PubMed
        30. Freeman MR. Glial (and neuronal) cells missing. Neuron. 2005 Oct 20; 48(2):163-5.
          View in: PubMed
        31. Freeman MR. Glial control of synaptogenesis. Cell. 2005 Feb 11; 120(3):292-3.
          View in: PubMed
        32. Freeman MR, Delrow J, Kim J, Johnson E, Doe CQ. Unwrapping glial biology: Gcm target genes regulating glial development, diversification, and function. Neuron. 2003 May 22; 38(4):567-80.
          View in: PubMed
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