Jing Hughes, an endocrinologist at Washington University in St. Louis, was working late in the lab recently, imaging cilia in mouse pancreatic beta cells. These cilia, which are tiny hairlike organelles, were thought to be static sensors that help the pancreas manage blood glucose levels, but nonmotile cilia in general are poorly characterized in comparison with their wiggly, moving counterparts. So, Hughes’ goal was to observe and record the distribution of these “primary” cilia within the organ’s well-defined clumps of cells, called islets. Then she saw one of them move.
“I didn’t believe it at first,” says Hughes. She had stayed late working on her microscopy, she explains, so “I thought I was just tired. These things were not supposed to move.”
I thought I was just tired. These things were not supposed to move.
—Jing Hughes, Washington University in St. Louis
Intrigued, Hughes and colleagues imaged pancreatic cilia under many different conditions, observing the same motion over and over again, the team reports (September 23) in Nature. The study marks the first time scientists have suggested that pancreatic cilia—indeed any primary cilia— can move as a result of force being generated inside the structures. This active motion, Hughes says, also has an important role in regulating insulin secretion.
The findings shocked the scientific community, Hughes tells The Scientist. The team’s close examination of the organelles revealed they are a hybrid of sorts between primary and motile cilia with molecular and structural aspects of both, upending the longstanding binary sorting of cilia. “We received pushback from the reviewers. . . . A lot of them challenged us to really defend our definition of this hybrid cilia [by asking] ‘How do you know it’s not an accident?’” she adds.
Ron Orbach, a biologist at Yale University who was not involved in the study, admits to being surprised too. “You have apples, you have oranges. Those are two different things. But now we see that there is also something in between,” he says.
After her late-night observation, Hughes and colleagues began their investigation by imaging primary cilia in human and mouse pancreatic islets. Each cilium is typically organized in a specific arrangement called “9+0,” where nine fused pairs of microtubules form a hollow cylinder. However, again to the scientists’ surprise, the cilia on pancreatic cells deviated from this expected arrangement and had eight outer microtubule doublets and a central microtubule doublet or singlet.
The researchers also used immunofluorescence microscopy to visualize proteins on live beta cells. They observed that the cilia contained motor proteins that are responsible for active motion in so-called motile cilia, the kind known to wiggle that are only observed in the lungs, the middle ear, and the respiratory tract. “This was again a big surprise. We thought maybe we’d find one or two [motor proteins]. We actually found a whole group of them,” says Hughes.
When Hughes and her team knocked out these proteins through targeted genetic deletion, the motion of the beta cells’ cilia ceased. And when the team exposed the motor protein–deficient beta cells to a bolus of glucose to trigger insulin secretion, they observed that a key step in that response—calcium influx—was delayed. This indicated to the researchers that the motor proteins were necessary for the cilia’s motion, and that these organelles weren’t moving passively based on the flow of fluids around them. Instead, they were looking at a previously unknown kind of cilia that could not only sense their environment but also respond to it by modulating the function of beta cells.
Although, according to Orbach, there’s more work to be done to uncover how the structural arrangement of this new type of cilium regulates its motion, he says this study has opened many new doors.
Hughes is similarly excited. Her group is currently focused on work that will further prove the functionality of the cilia’s motion inside a live animal model. “I think, as in every field, it takes a lot of work to kind of build up momentum to prove or disprove a dogma. . . . I’m hoping that a lot of colleagues will join forces and start looking into this question,” she says.