Cell Biology, Neuroscience
University of Massachusetts
Dr. Freeman is also a professor and vice chair of the Department of Neurobiology at the University of Massachusetts Medical School. Dr. Freeman was an HHMI early career scientist from 2009 to 2013.
Neuron-Glia Signaling in Nervous System Development, Function, and Disease
When Marc Freeman entered Eastern Connecticut State University, he planned to become a high school teacher, not a scientist. "Within six months, I fell in love with biology," he says.
In his sophomore year, a biology professor at the university, G. Michael Adams, invited him to take part in a research project on the alga Chlamydomonas. They worked together at the same bench and discussed biology, Freeman recalls. "I learned more from talking to him at that bench than in all my classes." Adams also suggested that Freeman attend graduate school, an option he says he'd never considered.
In the years since, Freeman, now at the University of Massachusetts, has become a champion of the most abundant, most mysterious cells in the nervous system. They are known as glia and have long been dismissed as the supporting cast for neurons. Freeman's research is helping glia get their due. "The exciting thing is that it's becoming more and more clear in many model systems that glia are playing very important roles in brain development and function and that they are often compromised in neurological disease," he says.
His interest in these overlooked cells dates to his postdoctoral research in the lab of HHMI Investigator Chris Doe at the University of Oregon. Freeman used genetic, genomic, and computational approaches to search for genes expressed in the glia of fruit flies and uncovered more than 80 genes that operate in glia—scientists had previously known about eight. "This treasure trove of genes to study has been keeping my lab busy for years," he says.
As an independent researcher, Freeman has been probing the functions of glia after injury. When part of the nervous system is damaged, glia, which come in several different types, speed to the site and help orchestrate repairs. One of their jobs is tidying up—they gobble up cellular debris. Freeman and his group identified the so-called Draper receptor, which in fruit flies detects the debris, and they defined much of the downstream molecular signaling pathway that spurs a glial cell to devour junk. Very recent work has revealed that Draper receptor signaling also occurs when mouse glia need to eat neuronal debris.
Freeman's lab also discovered that glia perform a vital job during the development of the nervous system, specifically during the formation of neuromuscular junctions. These synapses between nerves and muscles relay messages that trigger muscles to contract. Freeman and colleagues determined that as a neuromuscular junction develops, it sloughs off large amounts of cellular debris that can build up in the synapse. Clearance of that debris is important for normal synapse growth, he says. His team found that glia must handle the cleanup or the junction doesn't form properly.
Freeman, who became an HHMI early career scientist in 2009, has also followed glia in an unexpected direction that could illuminate what happens after a brain injury or during neurodegenerative diseases. To spur glia to clean up, his team created cellular debris by detaching axons, the signal-transmitting extensions of neurons. Normally, cut axons fall apart and glia rapidly devour them. However, Freeman's work reveals that in flies carrying certain mutations, the axons persist indefinitely. "Under the right conditions, it seems axons can live for a very long time on their own," he says. "How the axon, which can constitute more than 90 percent of the cell volume, can live without a nucleus for so long is a really interesting question." And one his group is keenly focused on.
He's also compelled to understand the nature of the pathway that normally drives the degeneration of axons after injury, since the process could go awry after brain damage and in neurodegenerative diseases. By studying the mutations that block this process, Freeman has identified a signaling pathway that transmits a message that promotes degeneration and encourages glia to devour the debris. "We think this is a normal part of nervous system maintenance," he says. For example, the brain might destroy an axon to shut down an unneeded connection between neurons.
Freeman and his group have also turned their attention to the least studied type of glial cells, the astrocytes. "This is potentially the most abundant cell type in our brain, but we have little idea of what it does," he says. One reason astrocytes have been hard to study is that researchers hadn't identified them in flies. Now, his group has pinpointed fly cells that appear to be the star-shaped astrocytes. Still, he has his work cut out for him studying these enigmatic cells, but that's what makes them intriguing, he says. "This is the kind of question that gets me interested—where there's almost a complete lack of information."