Glia (light green) respond to the loss of dendrite cilia (dark pink) by accumulating excess extracellular matrix (dark green).
Neurons may get all the glory, but they would be nothing without glial cells. While brain cells do the heavy lifting in the nervous system, it's the glia that provide nutrients, clean up waste, and protect neurons from harm.
Now, scientists have discovered a new mechanism by which these crucial supporting players detect and respond to neuron damage. Published in Nature Communications, the study describes how two key proteins allow glial cells to actively monitor the hair-like cilia that extend out of nematode dendrites, so that the glial cells can respond to injuries and prevent damage. The findings may have implications for treating diseases caused by defective cilia, such as polycystic kidney disease.
"Fleshing out the pathway by which glia interact with dendrites was our major goal," says Shai Shaham, head of the Laboratory of Developmental Genetics at Rockefeller. "An important next question is whether one could manipulate these cells to address diseases related to cilia."
Uncharted territory
Neurons rely on axons and dendrites for communication; axons send messages out, while dendrites receive those incoming, some with the help of cilia extending from their tips. Cilia detect odors, light, and other stimuli.
Scientists have studied how glial cells keep axons in shape. But comparatively few studies have investigated how glia protect and maintain dendrites and their delicate cilia. Knowing that dendrite structure changes correlate with learning and memory, and that dysfunctional cilia are at the heart of a family of disorders known as ciliopathies, Shaham and colleagues set out to fill that crucial knowledge gap .
"We knew essentially nothing about the interactions between glial cells and dendrites, but they matter just as much as axons," Shaham says. "You need something to receive signals, too."
The team chose to study glia, dendrites, and cilia in the nematode C. elegans, a model organism cherished by basic researchers for its straightforward genetics and well-studied biology. An additional advantage here was that nematodes have cilia only on the ends of their dendrites, simplifying the work of homing in on what happens to dendritic cilia when glia clock out. "C. elegans is a powerful model, because we can use it to explore everything from molecules to behavior," says Katherine Varandas, a postdoctoral fellow in Shaham's lab and lead author of the study. "Through studying nematodes we can decipher very specific dendrite and glia interactions."
Moving up the tree of life
For the study, the team used CRISPR to engineer nematodes with disrupted cilia or altered glial responses, and then tracked glia in-action using fluorescence microscopy. Then, to figure out how glia respond to normal and cilia-stunted nematodes, they employed RNA sequencing to monitor gene expression changes and electron microscopy to observe structural changes.
They found that glial cells respond to damaged cilia by accumulating excess extracellular matrix proteins and altering gene expression. Specifically, they discovered a new signaling pathway involving DGS-1, a neuronal protein, and FIG-1, a glial protein. These two proteins appear crucial to monitoring cilia integrity-mutations in either trigger glial responses even without cilia damage.
The findings broaden our understanding of glial functions, with potential implications extending far beyond nematodes. Indeed, the structural and functional similarities of sensory organs across species suggest that similar mechanisms for keeping cilia safe may exist in mammals, where glial cells have been shown to interact with similar dendritic structures. The present study could therefore lay the groundwork for exploring glia-dendrite interactions across species, with potential implications for humans suffering from ciliopathies.
"We hope to move these studies into mammals next," Varandas says. "Sensory organs, which include cilia-decorated dendrites surrounded by glia, are highly conserved across evolution and share striking similarities to one another, providing a fascinating direction for future research."
