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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 in the healthy and diseased brain. 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).

        Glia-neuron signaling in the healthy and diseased brain

        Neurons are not alone in the nervous system.  Glial cells constitute the majority of the cells in the human brain.  Despite their abundance, we know surprisingly little about how glia develop or function in the mature nervous system.  Understanding glial cell biology and neuron-glia interactions has become an important line of investigation contemporary neuroscience.  Exciting recent work from the field has demonstrated central roles for this enigmatic cell type in neural circuit assembly, function, and plasticity.  Moreover, glial cells appear to be primary responders to neuronal injury and neurodegenerative disease, but whether they are directly affected by disease, are responding to disease, or are in fact driving neuronal loss during disease remains unclear.  Defining the precise roles that glia play will be a crucial step if we wish understand how the nervous system is assembled, functions to drive animal behavior, and is maintained in a healthy state for the life of an animal. 

                    Our group uses the fruit fly Drosophila as a model system to explore fundamental aspects of glial cell biology.  The major advantages of the fly are its remarkable collection of molecular-genetic tools for the analysis of gene function, the depth of our understanding of the development, histology and function of the Drosophila nervous system, and the opportunity this system presents to perform forward genetic screens to identify molecules required for glia-neuron interactions in vivo.  Some of our key areas of focus include the following:

        1)  How do you make an astrocyte, and what does it do?  Astrocytes are the most abundant cell type in the mammalian brain.  We made the recent exciting discovery that astrocytes are also present in the Drosophila brain and are now using the fly to explore how these cells develop, the roles they play in neural circuit formation, and how astrocytes modulate brain function and behavior.

        2)  How do glial cells recognize and dispose of neuronal debris?  During normal development or after nervous system injury or disease, neuronal processes (axons, dendrites, and synapses) can degenerate and neuronal cell bodies often undergo apoptotic cell death.  Glial cells are the primary cell type responsible for recognizing and clearing this neuronal debris.  We are interested in understanding how neurons signal to glia to indicate debris is present and needs clearance, and the molecular basis of glial recognition and phagocytosis of neuronal debris. 

        3)  How are long axons wrapped and supported by glia?  Long axons in mammals in flies are surrounded, and often individually ensheathed, by glial processes.  Such insulation is thought to be critical for enhanced nerve conduction velocity and trophic support of long axons that are some distance from the cell body.  We are exploring the molecular basis of axonal ensheathment in Drosophila and the mechanisms by which surrounding glial cells promote the survival and function of the axons they ensheath.

        4)  How do axons undergo auto-destruction?  Severed axons (and dendrites) degenerate after axotomy, but is this a passive wasting away or an active death process?  We recently discovered that deletion of the dSarm/Sarm1 gene resulted in the long-term survival of the distal portions of severed axon in both flies and mice.  This work provided direct evidence for the existence of a dSarm/Sarm1-dependent axon death signaling pathway.  We are now using powerful molecular approaches in Drosophila to identify additional axon death genes, and exploring the role of axon death signaling in neuron loss during disease using both fly and mouse models of neurological disorders.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Muthukumar AK, Stork T, Freeman MR. Activity-dependent regulation of astrocyte GAT levels during synaptogenesis. Nat Neurosci. 2014 Aug 24.
          View in: PubMed
        2. Lu TY, Doherty J, Freeman MR. DRK/DOS/SOS converge with Crk/Mbc/dCed-12 to activate Rac1 during glial engulfment of axonal debris. Proc Natl Acad Sci U S A. 2014 Aug 26; 111(34):12544-9.
          View in: PubMed
        3. Burdett TC, Freeman MR. Neuroscience. Astrocytes eyeball axonal mitochondria. Science. 2014 Jul 25; 345(6195):385-6.
          View in: PubMed
        4. 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
        5. 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
        6. Freeman MR. Signaling mechanisms regulating Wallerian degeneration. Curr Opin Neurobiol. 2014 Aug; 27C:224-231.
          View in: PubMed
        7. 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
        8. Rooney TM, Freeman MR. Drosophila models of neuronal injury. ILAR J. 2014 Jan; 54(3):291-5.
          View in: PubMed
        9. 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
        10. 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
        11. 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
        12. 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
        13. Macdonald JM, Doherty J, Hackett R, Freeman MR. The c-Jun kinase signaling cascade promotes glial engulfment activity through activation of draper and phagocytic function. Cell Death Differ. 2013 Sep; 20(9):1140-8.
          View in: PubMed
        14. 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
        15. 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
        16. 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
        17. 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
        18. 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
        19. 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
        20. 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
        21. Freeman MR. Specification and morphogenesis of astrocytes. Science. 2010 Nov 5; 330(6005):774-8.
          View in: PubMed
        22. 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
        23. Coleman MP, Freeman MR. Wallerian degeneration, wld(s), and nmnat. Annu Rev Neurosci. 2010; 33:245-67.
          View in: PubMed
        24. Osterloh JM, Freeman MR. Neuronal death or dismemberment mediated by Sox14. Nat Neurosci. 2009 Dec; 12(12):1479-80.
          View in: PubMed
        25. 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
        26. 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
        27. 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
        28. 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.
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        29. Emery P, Freeman MR. Glia got rhythm. Neuron. 2007 Aug 2; 55(3):337-9.
          View in: PubMed
        30. 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
        31. Freeman MR. A look inside. Neuron Glia Biol. 2007 Feb; 3(1):1-3.
          View in: PubMed
        32. 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
        33. Freeman MR, Doherty J. Glial cell biology in Drosophila and vertebrates. Trends Neurosci. 2006 Feb; 29(2):82-90.
          View in: PubMed
        34. Freeman MR. Sculpting the nervous system: glial control of neuronal development. Curr Opin Neurobiol. 2006 Feb; 16(1):119-25.
          View in: PubMed
        35. Freeman MR. Glial (and neuronal) cells missing. Neuron. 2005 Oct 20; 48(2):163-5.
          View in: PubMed
        36. Freeman MR. Glial control of synaptogenesis. Cell. 2005 Feb 11; 120(3):292-3.
          View in: PubMed
        37. 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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