Nearly every cell in your body is releasing microscopic bubbles that contain tiny messages to other cells in your body. The bubbles are so small that if a cell were the size of the Empire State Building, the vesicles would be the size of teenage couriers, running to deliver messages to neighboring buildings in the organism of Manhattan. But now there's evidence that at least in worms, these little bubbles, called extracellular vesicles (ECVs), can leave the cells of the Manhattan Island worm to deliver messages to cells in the Brooklyn worm. The first of these external messages to be discovered turns out to be a love note.
Juan Wang, a research assistant professor at Rutgers University, and Maureen Barr, a professor at Rutgers University and an ASCB member, in collaboration with researchers at Albert Einstein College of Medicine, reported in the March Current Biology that the laboratory system model worm, Caenorhabditis elegans, releases ECVs that impact mating behavior in other worms. This is a radically new function for ECVs, which are generally thought to communicate between cells within an organism. This is the first time ECVs have been shown to be a means of communication between separate organisms.
The discovery was unexpected, Barr said. The connection came through her studies of polycystin proteins in worms. In humans, mutations in polycystin genes are linked to polycystic kidney disease (PKD). "We can never say C. elegans is a model system of PKD because C. elegans don't have kidneys," Barr explained, and yet in C. elegans and humans, the polycystin genes act in analogous genetic pathways, have similar protein sequences, and get to the same place in the cells. "There's some really basic biology that we can get at in C. elegans," Barr said.
The ECV story took years to percolate. Barr made the first observation over a decade ago but dismissed it. Working in C. elegans, Barr noticed particles coming out of the nose and tail of worms under the microscope. More than a year later Wang, then a postdoc, became intrigued by Barr's observation and decided to investigate. "At the same time we were going to kidney, cell biology, and cilia meetings, and became aware of the ECVs in [mammalian] urine that contain polycystin proteins," Barr said. It seemed too well aligned with their observations to be a coincidence.
The new paper shows that ECVs are released from the tip of the worm's nose and its tail rays. Imagine a spiked baseball bat—the spikes are the rays, the bat is the tail. Here the worm exposes neurons each with a single cilium. The cilia are structures like long antennae on top of skyscrapers. Like antennae, the cilia collect and transmit signals. The researchers found that the ECVs are released from the base of each cilium, containing the cilia-associated polycystin proteins that Barr and Wang knew from their previous studies.
What these ECVs were doing outside the worm was a mystery for a while. But Joel Rosenbaum, professor at Yale University who showed that Chlamydomonas release flagellar ectosomes, encouraged Barr's lab to figure out the function of the worm ECVs. Barr said, "It could be that [the worms] were just dumping out protein garbage, but ECVs have been shown to be important in intercellular signaling in mammals." Barr added, "We thought of the ECVs as the worm equivalent of sneezing all over the place, or marking their territory." So they decided to see what happened when other worms came in contact with patches of ECVs.
Crawling over a patch of ECVs from another worm was an exciting experience, at least for the traveling worm, Barr reports. Their tails would curl and the worms would start chasing their own tails. Most C. elegans are hermaphrodites, reproducing asexually but there are also rare male C. elegans that give the species a way to reproduce sexually, providing genetic variety that self-fertilizing hermaphrodites alone cannot. Tail curling allows male worms to contact and circle around hermaphrodites during mating. Since male C. elegans are so rare in nature, these ECV-triggered behaviors may be aimed at optimizing reproductive success, Barr said.
ECVs are also released by almost all the cells in the human body, and outside the body in urine, seminal fluid, and breast milk. "I suspect they're going to play a role in communication [in other animals], but really the challenge is going to be detecting the interaction between the ECV and the cell. We have a real advantage with C. elegans; we can address that question in a simple model system," Barr said.
Wang J, Silva M, Haas LA, Morsci NS, Nguyen KC, Hall DH, & Barr MM (2014). C. elegans Ciliated Sensory Neurons Release Extracellular Vesicles that Function in Animal Communication. Current biology : CB, 24 (5), 519-25 PMID: 24530063
This work was supported by NIH R01DK059418, NIH R01DK074746, and by NIH OD010943.