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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.
McPhee CK, Logan MA, Freeman MR, Baehrecke EH (2010) Activation of autophagy during cell death requires the engulfment receptor Draper. Nature, In Press.
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.