Marc Freeman, PhD
Professor and Vice Chair
703 Lazare Research Bldg
Dept of Neurobiology
Howard Hughes Medical Institute
University of Massachusetts Medical School
Worcester, MA 01605
office 508 856 6136
lab 508 856 3711
Faculty page: http://profiles.umassmed.edu/profiles/ProfileDetails.aspx?From=SE&Person=845
Molecular mechanisms of axon auto-destruction
We are 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 forward genetic analysis of axon auto-destruction pathways. We are now deeply immersed in trying to understand (1) the signaling pathways that actively drive axon auto-destruction; (2) how Wlds protects severed axons from auto-destruction; and (3) the molecular identity of axonal injury signals that activate glial responses.
MacDonald, J., Beach, M., Porpiglia, E., Sheehan, A.E., Watts, R.E., and M.R. Freeman. (2006) The Drosophila cell corpse engulfment receptor Draper mediates glial clearance of severed axons. Neuron, 50, 869-881.
Ziegenfuss, J.S., Biswas, R., Avery, M.A., Sheehan, A.E., Stanley, E.R., and M.R. Freeman (2008) Draper-dependent glial phagocytic activity is mediated by Src and Syk family kinase signaling pathways. Nature, 453, 935-939.
Avery, M.A., Tasdemir, O., Sheehan, A., Wang, J., and M.R. Freeman. (2009) Wlds requires Nmnat1-dependent NAD biosynthetic activity and N16-VCP interactions to suppress Wallerian degeneration. J. Cell Biology 184 (4), 501-513.
Doherty, J., Logan, M.A., Tasdemir, O., and M.R. Freeman (2009) Ensheathing Glia Function as Phagocytes in the Adult Drosophila Brain. J. Neuroscience, 29, 4768-81.
Fuentes-Medel, Y., Logan, M.A., Ataman, B., Budnik, V., and M.R. Freeman (2009) Glia and muscle sculpt connectivity at the neuromuscular junction by engulfing shed presynaptic debris and eliminated synapses. PLoS-Biology, 7(8):e1000184.