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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 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.

One or more keywords matched the following items that are connected to Freeman, Marc
Item TypeName
Academic Article Unwrapping glial biology: Gcm target genes regulating glial development, diversification, and function.
Academic Article Glial control of synaptogenesis.
Academic Article Sculpting the nervous system: glial control of neuronal development.
Academic Article The Drosophila cell corpse engulfment receptor Draper mediates glial clearance of severed axons.
Academic Article Wld S requires Nmnat1 enzymatic activity and N16-VCP interactions to suppress Wallerian degeneration.
Academic Article Glia and muscle sculpt neuromuscular arbors by engulfing destabilized synaptic boutons and shed presynaptic debris.
Academic Article Wallerian degeneration, wld(s), and nmnat.
Academic Article Activation of autophagy during cell death requires the engulfment receptor Draper.
Academic Article Negative regulation of glial engulfment activity by Draper terminates glial responses to axon injury.
Academic Article dSarm/Sarm1 is required for activation of an injury-induced axon death pathway.
Academic Article Glial (and neuronal) cells missing.
Academic Article Glial cell biology in Drosophila and vertebrates.
Academic Article Draper-dependent glial phagocytic activity is mediated by Src and Syk family kinase signalling.
Academic Article Ensheathing glia function as phagocytes in the adult Drosophila brain.
Academic Article Neuronal death or dismemberment mediated by Sox14.
Academic Article Specification and morphogenesis of astrocytes.
Academic Article Analysis of glial cell development and function in Drosophila.
Academic Article WldS prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca2+ buffering.
Academic Article Distinct molecular pathways mediate glial activation and engulfment of axonal debris after axotomy.
Academic Article Combining comparative proteomics and molecular genetics uncovers regulators of synaptic and axonal stability and degeneration in vivo.
Academic Article Deletions within its subcellular targeting domain enhance the axon protective capacity of Nmnat2 in vivo.
Concept Disease Models, Animal
Concept Wings, Animal
Concept Animals
Concept Behavior, Animal
Concept Animals, Genetically Modified
Academic Article Probing the enigma: unraveling glial cell biology in invertebrates.
Academic Article Evolving concepts of gliogenesis: a look way back and ahead to the next 25 years.
Academic Article Cell biology in neuroscience: Architects in neural circuit design: glia control neuron numbers and connectivity.
Academic Article Astrocytes engage unique molecular programs to engulf pruned neuronal debris from distinct subsets of neurons.
Academic Article Glial wingless/Wnt regulates glutamate receptor clustering and synaptic physiology at the Drosophila neuromuscular junction.
Academic Article Drosophila models of neuronal injury.
Academic Article Rapid in vivo forward genetic approach for identifying axon death genes in Drosophila.
Academic Article Neuron-glia interactions through the Heartless FGF receptor signaling pathway mediate morphogenesis of Drosophila astrocytes.
Academic Article DRK/DOS/SOS converge with Crk/Mbc/dCed-12 to activate Rac1 during glial engulfment of axonal debris.
Academic Article Signaling mechanisms regulating Wallerian degeneration.
Academic Article Activity-dependent regulation of astrocyte GAT levels during synaptogenesis.
Academic Article PI3K signaling and Stat92E converge to modulate glial responsiveness to axonal injury.
Academic Article Age-Dependent TDP-43-Mediated Motor Neuron Degeneration Requires GSK3, hat-trick, and xmas-2.
Academic Article Drosophila Central Nervous System Glia.
Academic Article Attenuated traumatic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1.
Academic Article Prevalent presence of periodic actin-spectrin-based membrane skeleton in a broad range of neuronal cell types and animal species.
Academic Article Neuromodulators signal through astrocytes to alter neural circuit activity and behaviour.
Academic Article Axon degeneration induces glial responses through Draper-TRAF4-JNK signalling.
Academic Article Loss of Sarm1 does not suppress motor neuron degeneration in the SOD1G93A mouse model of amyotrophic lateral sclerosis.
Academic Article The secreted neurotrophin SpƤtzle 3 promotes glial morphogenesis and supports neuronal survival and function.
Academic Article Transcription factor Pebbled/RREB1 regulates injury-induced axon degeneration.
Academic Article Focal adhesion molecules regulate astrocyte morphology and glutamate transporters to suppress seizure-like behavior.
Academic Article Axon Death Pathways Converge on Axundead to Promote Functional and Structural Axon Disassembly.
Academic Article Glutathione S-Transferase Regulates Mitochondrial Populations in Axons through Increased Glutathione Oxidation.
Academic Article Polymodal Nociception in Drosophila Requires Alternative Splicing of TrpA1.
Academic Article Live-imaging of astrocyte morphogenesis and function in zebrafish neural circuits.
Academic Article Injury-Induced Inhibition of Bystander Neurons Requires dSarm and Signaling from Glia.
Academic Article TrpML-mediated astrocyte microdomain Ca2+ transients regulate astrocyte-tracheal interactions.
Academic Article Behaviorally consequential astrocytic regulation of neural circuits.
Academic Article Astrocytes close a motor circuit critical period.
Academic Article TSG101 negatively regulates mitochondrial biogenesis in axons.
Academic Article SARM1 signaling mechanisms in the injured nervous system.
Academic Article An ELISA-based method for rapid genetic screens in Drosophila.
Academic Article Astrocytic GABA transporter controls sleep by modulating GABAergic signaling in Drosophila circadian neurons.
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