New findings on nematodes shed light on how glial cells watch over and support neuronal dendrites.
While neurons often capture attention, they owe a great deal to glial cells. These supportive brain cells play a vital role by providing nutrients, clearing waste, and safeguarding neurons from damage.
Recent research published in Nature Communications has unveiled a new way these essential support cells detect and address neuron injury. The study illustrates how two important proteins enable glial cells to actively oversee the hair-like cilia that project from nematode dendrites, allowing them to respond to damage and protect the neurons. This discovery could have significant effects on treatments for diseases linked to defective cilia, like polycystic kidney disease.
“Our primary aim was to understand how glia interact with dendrites,” says Shai Shaham, director of the Laboratory of Developmental Genetics at Rockefeller. “A key next question is whether it’s possible to modify these cells to tackle diseases associated with cilia.”
Exploring New Frontiers
Neurons depend on axons and dendrites for communication; axons transmit signals while dendrites take them in, aided by cilia at their tips. Cilia are responsible for sensing odors, light, and other stimuli.
While research has focused on how glial cells assist axons, much less attention has been given to their role in maintaining and defending dendrites and their fragile cilia. Recognizing that alterations in dendrite structure are linked to learning and memory, and that dysfunctional cilia are central to a group of disorders known as ciliopathies, Shaham and his team aimed to bridge this important knowledge gap.
“We basically had no insights into how glial cells and dendrites interacted, but these interactions are just as vital as those involving axons,” Shaham explains. “There needs to be a mechanism for receiving signals as well.”
The researchers focused on the glia, dendrites, and cilia in the nematode C. elegans, a favorite among researchers for its clear genetics and well-documented biology. An added benefit is that nematodes possess cilia only at the ends of their dendrites, making it easier to study the effects of glial deactivation on dendritic cilia. “C. elegans is a robust model, as it allows us to explore a wide range of concepts from molecular to behavioral levels,” says Katherine Varandas, a postdoctoral fellow in Shaham’s lab and the study’s lead author. “By studying nematodes, we can uncover intricate interactions between dendrites and glia.”
Ascending the Tree of Life
For their investigation, the team employed CRISPR technology to create nematodes with malfunctioning cilia or modified glial reactions. They then observed the glial cells in action using fluorescence microscopy. To determine how glia react to both normal and impaired cilia in nematodes, they utilized RNA sequencing to examine changes in gene expression and electron microscopy to detect structural alterations.
The team discovered that glial cells respond to cilia damage by building up excess extracellular matrix proteins and changing gene expression patterns. They identified a new signaling pathway involving DGS-1, a neuronal protein, and FIG-1, a glial protein. These proteins play a vital role in overseeing cilia health, as mutations in either can activate glial responses even in the absence of cilia injury.
This research enhances our comprehension of glial functions with potential applications extending well beyond nematodes. Given the structural and functional parallels of sensory organs in different species, similar protective mechanisms for cilia may also be present in mammals, where glial cells interact with similar dendritic formations. Consequently, this study could pave the way for further exploration of glia-dendrite interactions across various species, potentially benefiting those with ciliopathies in humans.
“We aim to extend this research to mammals next,” Varandas mentions. “Sensory organs, featuring cilia-laden dendrites accompanied by glial cells, have evolved in a remarkably conserved manner, presenting exciting avenues for future studies.”
