Every multicellular organism, from tiny worms to humans, elephants and whales, needs a way for their cells to work together.
Cells have a variety of protein receptors on their surfaces that connect with receptors on other cells to form so-called adhesive structures. These help them communicate and respond to cues from their environment. The sum of these interactions is called the cell surface “interactome,” which serves as a reference manual for understanding how these tiny units coordinate—and ultimately form tissues and organs, and organize their overall body plan.
In a recent study published in Cell Genomics, scientists from the University of Chicago published the first extracellular interactome for the nematode worm Caenorhabditis elegans, a classic model organism for studying genetic and cellular development. The data describes extracellular interactions for 374 proteins, including 159 interactions that were previously unknown, revealing unexpected connections involved in neuron development and insulin signaling.
For Engin Özkan, an associate professor of biochemistry and molecular biology at UChicago and senior author of the paper, building this interactome has been a decade-long quest.
“Multicellular life is one complex manual—so many parts have to come together. The cells need to get to the right place to perform and have the correct molecules to connect with other molecules from surrounding tissues and other cells,” he said. “We've been missing so much of this blueprint because we lacked the basic data about which molecules interact with which. And that's the gap my lab has been trying to fill for the last 10 years, so that we can understand how the synaptic connections between all neurons form.”
Why C. elegans matters for human biology
While the tiny—less than 1 mm long—C. elegans worm couldn’t look more different from complex multicellular animals such as humans, it’s a powerful and beloved scientific model.
Simplicity helps—an adult worm has about 1,000 cells, with exactly 302 neurons, all carefully mapped and genetically sequenced. They are easily manipulated with modern genetic tools, plus they grow quickly and are easy to maintain, making them ideal experimental animals.
Despite these differences, many molecular pathways—including processes for cell death, aging, metabolism and development—work the same way in both organisms, making discoveries in worms relevant to human biology.
“You would think by 2026, we would know the majority of interactions that hold this animal’s cells together, but we still don't, which is an opportunity for a lab like mine,” Özkan said.
As a structural biologist by trade, his lab specializes in building a variety of biochemical tools, imaging techniques, protein engineering strategies and genetic modifications to document and decipher the surface receptors that help cells connect to each other.
Most surface receptors are embedded in cell membranes made from lipids, which pose a lot of technical challenges for researchers trying to study them. Özkan’s team has developed several biochemical tools that allow them to study these receptors at high volume, uncovering as much as 80% of their interactions that hadn’t been discovered yet.
Asst. Prof. István Kovács’s group at Northwestern University also contributed novel mathematical analysis methods for the study, which was a collaboration made possible by the National Institute for Theory and Mathematics in Biology, a joint partnership between the two universities.
New cell interactions point toward disease research
The research uncovered several protein families that interact in unexpected ways, including one group thought to be involved in neuron growth that also participates in insulin signaling.
Experiments that increased the expression of these proteins also extended the lifespan of the worms. Other new interactions had unexpected roles in signaling for growth factors.
Since so many of these receptors are similar in humans, understanding how they work is important for understanding what they do—and, more importantly, what happens when something goes wrong and leads to disease.
Combining this new set of interaction data (the interactome) with decades of work cataloging C. elegans genes (the genome) and gene expression (the transcriptome) builds a more complete reference manual for understanding basic biology.
“The modern biologist is often after this thing we call mechanism, or how it works,” Özkan said. “Now at least for cell surface molecules, we know what those molecules are supposed to interact with. Now we have good ideas about how to connect that to function, through decades of genetics work by others, and begin to complete the circle into a full understanding of multicellular function.”
The study, “Nematode extracellular protein interactome expands connections between signaling pathways,” was supported by the National Institute for Theory and Mathematics in Biology; the National Science Foundation; and the Simons Foundation. Additional authors include Wioletta I. Nawrocka, Shouqiang Cheng, Matthew C. Rosen, Elena Cortés, Elana E. Baltrusaitis and Zainab Aziz from UChicago; Leo T.H. Tang from the University of Vermont; and Bingjie Hao and István A. Kovács from Northwestern.
—This article was originally published on the Biological Sciences Division website.
