NEURON-GLIAL SIGNALING IN DEVELOPMENT AND DISEASE
In the mammalian brain, glial cells outnumber neurons 10:1. Despite their abundance, we know surprisingly little about how glial cells communicate with neurons to regulate proper development and function of the nervous system. One striking and conserved attribute of glia is their ability to sense and respond to changes in neuronal health. Glia respond swiftly to brain trauma, including acute injury and neurodegenerative disease, by infiltrating trauma sites and clearing damaged neurons through phagocytic engulfment. These glial responses walk a fine line between being helpful and destructive; although important for minimizing post-traumatic damage, glia may also exacerbate the progression of some neurodegenerative disorders, such as Alzheimer’s.
Our lab uses molecular, genetic, and imaging approaches in the experimentally tractable fruit fly Drosophila melanogaster to explore the molecular underpinnings of glial responses to neural injury. If we acutely trigger axon degeneration in the adult fly by mechanically severing the antennal nerve that projects into the brain, glia accumulate on the severed axons (Figure 1, arrows) and clear axonal debris from the brain. Exciting questions that we are tackling include: (1) What signals are produced by degenerating neurons? (2) How do glial cells distinguish degenerating from healthy neurons? (3) What are the cellular pathways that control glial migration to trauma sites and the phagocytic activity of glial cells?
The Draper receptor can activate and inhibit glial engulfment activity
The transmembrane receptor Draper is required for glia to clear degenerating neurons in the adult fly, but precisely how Draper contributes to glial engulfment activity is still unclear. We recently discovered that Draper can tightly control glial responses to axon degeneration by activating and inhibiting glial engulfment activity through signaling of distinct receptor isoforms. One isoform, Draper-I, triggers glial engulfment of degenerating axons and signals through an intracellular immunoreceptor tyrosine-based activation motif (ITAM) and recruitment of a tyrosine kinase. Interestingly, a second isoform, Draper-II, inhibits phagocytic activity through its unique immunoreceptor tyrosine-based inhibitory motif (ITIM) and the effector protein, the tyrosine phosphatase Corkscrew. ITAM and ITIM-bearing receptors can antagonistically control immune responses in professional immune cells (e.g. mammalian macrophages), suggesting that fly glia employ classic immune signaling pathways when mounting a response to damaged neurons. In future work, we will explore how Draper-I and Draper-II activity is differentially regulated within glia.
New players in the glial response to neurodegeneration
To identify novel molecules involved in glial responses to neural injury, we are performing a large-scale forward genetic screen and testing candidate molecules by RNA interference (RNAi). This strategy is revealing exciting new factors that are required for glia to sense and/or respond to degenerating neurons. Figure 2 depicts one of our new mutants in which glia fail to engulf degenerating axons after axotomy.
Our work will provide exciting new insight into how glia contribute to post-injury events and identify potential therapeutic targets for the future treatment of brain trauma and chronic neurodegenerative conditions. In addition, it is clear that some neuron-glia signaling events after injury and the associated signaling pathways (such as Draper) are relevant to many aspects of nervous system development. Thus, our discoveries regarding glial responses to neurodegeneration in the adult will provide important clues as to how glia help shape the developing CNS through clearance of apoptotic cells and remodeling of neuronal networks.
Osterloh JM, Yang J, Rooney T, Powell EH, Fox N, Sheehan A, Avery M, Hackett R, Logan MA, MacDonald J, Ziegenfuss JS, Adalbert R, Hou Y, Nathan C, Ding A, Brown, Jr. R, Coleman M, Zuchner S, Tessier-Lavigne M, Freeman MR (2012) dSarm/Sarm1 governs a novel injury-induced axon death pathway. Science (in press).
McPhee CK, Logan MA, Freeman MR, Baehrecke EH (2010) Activation of autophagy during cell death requires the engulfment receptor Draper. Nature 465, 1093-1096.
Fuentes-Medel Y, Logan MA, Ashley J, Ataman B, Budnik V, Freeman MR (2009) Glia and muscle sculpt neuromuscular arbors by engulfing destabilized synaptic boutons and shed presynaptic debris. PLoS Biol 7(8), e1000184.Doherty J*, Logan MA*, Tasdemir OE, Freeman MR (2009) Ensheathing glia function as phagocytes in the adult Drosophila brain. J Neurosci 29, 4768-81. *co-first authors
Logan MA, Freeman MR (2007) The scoop on the fly brain: glial engulfment functions
in Drosophila. Neuron Glia Biol 3, 63-74.
Mary A. Logan
Ph.D., University of Utah, 2005
Postdoctoral Fellow, University of Massachusetts Medical Center, 2005-2010
Dr. Logan joined the Jungers Center as an Assistant Scientist and Assistant Professor of Neurology in September 2010. She earned a B.S. in neuroscience from Trinity College in Hartford, CT. After working at NPS Pharmaceuticals, Inc. in Salt Lake City for several years, Dr. Logan entered graduate school at the University of Utah where she did her Ph.D. thesis work with Monica Vetter studying gene transcription networks that regulate nervous system development. She then joined Marc Freeman’s lab at the University of Massachusetts Medical School in Worcester, MA as a postdoctoral fellow to explore immunological activity of glial cells in the fruit fly Drosophila melanogaster. Her work has identified signaling pathways that control glial cell recognition and phagocytosis of degenerating axons, which occurs following trauma, including ischemia and degenerative diseases such as multiple sclerosis. Dr. Logan will continue to take advantage of fly genetics to examine new molecules involved in neuronal-glial interactions in the healthy and diseased brain.
Jungers Center for Neurosciences Research
Department of Neurology - Mail Cod L623
Oregon Health & Science University
3181 S.W. Sam Jackson Park Road
Portland, Oregon 97239
Phone: (503) 418-1568
PhD, University of Utah
Postdoctoral Fellow, University of Massachusetts
I received my PhD in Molecular Biology from the University of Utah in 2005. My scientific interests are driven by where the biology leads me and where a microscope allows me to go. My graduate work was split between two model systems, Drosophila and C. elegans. In both systems I concentrated on the molecular mechanisms of synaptic transmission and its modulation. I studied the role of the ubiquitin proteasome systems (UPS) and local protein degradation as a mechanism to temporally regulate synaptic transmission at the Drosophila neuromuscular junction. My work in C. elegans focused on the regulation of dense core vesicle release and the downstream pathways activated by neuropeptides. During my postdoctoral work at UMASS Medical School I studied a pathway that regulates activity dependent synapse to nuclear signaling. This work has led to the discovery of an endogenous nuclear mRNA export pathway that was previously though to be utilized only by viruses. Now as a Research Assistant Professor at OHSU, I am again using Drosophila as a model to explore the molecular mechanisms of adult neurodegeneration in both the central and peripheral nervous system. I am also interested in understanding how glial cells influence neuronal connectivity and activity in the developing nervous system.
E. Jolanda Muenzel
M.D., Medical University of Vienna, Austria
Ph.D. University of Edinburgh, United Kingdom
With a medical doctorate degree and a Ph.D. in neuroscience, I am very interested in central nervous system diseases, in particular using in vivo model organisms to study the role of glia in neurodegenerative pathology. During my Ph.D., my research focused on exploring remyelination in zebrafish, a model organism which is known for its tremendous regenerative capacity. I characterized a new transgenic line expressing the novel myelin marker Claudin k, and used this platform to investigate remyelination in adult zebrafish after injury and to test hypotheses with regard to the biological mechanisms underpinning oligodendrocyte precursor recruitment. My work made novel discoveries around the differences in remyelination potential of young and old zebrafish and putative signaling pathways involved in mediating remyelination. To further follow my interests in glial biology, I have joined the Logan lab for a post-doctoral fellowship during which I will explore the role of glia in remodeling neural circuits in the adult fly brain.
BS, Furman University
My interest in science started at a very early age with my mother reading Zoobooks to me before bed every night. In kindergarten, when asked what I wanted to be when I grew up, I would say "zoologist" and thought that was a perfectly normal answer... so it started early. Some years later, I attended college at Furman University, nestled in the beautiful foothills of the Appalachians in South Carolina. I started out as a chemistry major and worked in the lab of Paul Wagenknecht on problems of inorganic chemistry. By pure happenstance, in my sophomore year I took a class taught by Bill Blaker on neuroscience. By the end of the course, I had changed my major-- I was officially hooked on the brain! I went on to work in Bill's lab studying neuronal circuits involved in short-term memory formation. After moving on to graduate school at OHSU, I joined the Logan lab where I am now studying the underlying molecular mechanisms that control glial responses to injury in the brain.
BS, University of Oregon
I received a BS in Biology from the Robert D. Clark Honors College at the University of Oregon in 2010. During my undergraduate career, I worked in Dr. Chris Doe’s lab, where I helped identify neuronal patterns of late-stage Drosophila embryos to help generate a neuronal atlas of gene expression in the embryonic fly CNS. I continued this project at Janelia Farms Research Campus in Dr. Gerry Rubin’s lab as a Janelia Undergraduate Scholar. During the last year of my undergraduate work, I shifted my research focus to explore how central pattern generators can be visualized and manipulated during Drosophila larval locomotion. As a graduate student in the Logan lab, I am now working with adult Drosophila and studying the signals that degenerating neurons release to elicit immune responses in glial cells. I am also studying the affects of aging on the ability of glia to respond to brain injury.
BS, University of Rochester
I received a BS in Neuroscience from the University of Rochester in 2011. As an undergraduate, I worked in Steve Goldman's lab studying oligodendrocyte precursor cells. I became interested in neuroscience in college during my freshman introductory psychology class when I realized how integral proper brain function is to human well-being. As I learned more, i developed a strong interest in studying glia because there is still so much to learn about this cell type. In the Logan Lab, I am excited to use Drosophila to investigate glial-neuronal interactions.