Although they comprise 80 percent of all human brain cells, glial cells have been overlooked by many neuroscientists who thought they mainly played supporting roles to neurons.
But recently, glial cells have emerged as essential regulatory players in nervous system development, function, and health. Marc Freeman of the University of Massachusetts Medical School has played an important part in defining key roles for glial cells in cell-to-cell communication in the nervous system and in how the brain recovers from injury.
Freeman’s interest in glia dates back to his days as a postdoctoral fellow at the University of Oregon in the laboratory of HHMI investigator Chris Doe. Doe’s lab focuses on studying the development of the central nervous system in the fruit fly Drosophila melanogaster. “There was an amazing new set of genomic tools available following the sequencing of the fruit fly genome,” says Freeman. “I saw the opportunity to use those tools to address some really fundamental questions of neurobiology—How do you make glia? What are they doing in the brain?”
Because so little was known about glia and he was convinced flies could be a good model to study them, Freeman asked his adviser whether he could apply these new tools to studying glial development and function. Doe agreed and told Freeman (with tongue firmly in cheek): “Just make sure you take it all with you when you leave the lab.”
First in Doe’s lab, and then as an independent investigator, Freeman identified a subset of genes that are expressed only in glia and thus serve as markers for these cells. These markers have allowed him to determine that the astrocyte, a star-shaped glial cell that is most prevalent in mammals, is also present in the fruit fly brain.
Astrocytes are known to function at synapses, the small gaps separating neurons where information flows from one neuron to another. Finding that astrocytes also exist in flies means that Freeman can use the impressive array of molecular genetic tools available in Drosophila to study their functions in neuronal signaling. “Most researchers considered synaptic signaling as purely a communication between presynaptic neuron and postsynaptic neuron with little contribution from glia,” says Freeman. “Emerging work argues that glia are involved in the regulation, formation, maturation, and firing of synapses. We hope to use flies to define the molecules that allow glia to regulate these events.”
Freeman is also using fruit flies to study how glial cells help clean up neurological “waste.” In mammals, when a neuron’s long projection—or axon—is cut, it withers away through a process called Wallerian degeneration. When that happens, glia flood the injury site and engulf degenerating axons, essentially cleaning up debris.
Freeman has shown that a similar process occurs in fruit flies. He wants to identify the biochemical cues that allow glia to recognize debris from degenerating axons as waste products and engulf them. Recent work has shown that injured axons, from flies to mammals, may initiate an autodestruction program, which could then signal the glia to act. Freeman is looking for the genes that drive both axonal destruction and glial activation.
Glia are also responsible for cleaning up other types of damage, such as neurons that undergo programmed cell death, or apoptosis, and neurons killed by lack of oxygen. Freeman has made headway in identifying the molecular pathways involved in this cleaning up process. In a recent study in Drosophila, he showed that, for glia to flock to an injury site, they must increase expression of an “engulfment receptor” called Draper on their surface. In mutant flies that lack Draper, glia fail to respond to injury, and debris is not cleared away.
Freeman thinks that these types of experiments will help pull glia enthusiasts onto neuroscience’s center stage. “We’re finding more and more evidence that glia do much more than just serve neurons, and we’re happy to get the word out,” he says.