For many organisms, everything needed for growth and metabolism is confined neatly within a single entity: the cell, fundamental unit of life. Many single-celled organisms wade through the world in solitude, but the story is quite different for organisms made up of many cells, including ourselves. Our cells sense and respond to their environment—and they react to each other as well.

One important part of communication between cells is to determine whether they will stick together or move away from each other. These decisions result in the creation of borders between groups of cells and are the reason our insides actually consist of defined structures like muscles, organs, and blood vessels instead of just looking like a pile of ground beef.

A family of proteins, called ephrins, is vital for maintaining these borders within the body. When ephrin proteins on adjacent cells get close enough, they bind tightly to one another. Like pixels forming pictures or words on a screen, the sum of all the ephrins interacting in an area is more consequential than a single ephrin is. When two cells meet, all the ephrin interactions put together are decoded into a response. While the complexity of how cells interpret ephrin signals is still actively being investigated, the most common response is for the two cells to move away from each other.

These cells now find themselves in a predicament. They have made the decision to pull away, but are still physically tethered by tightly bound ephrin proteins. Fortunately, this type of cell-to-cell communication comes with a built-in contingency plan. Enzymes that cut proteins (proteases) are brought to the ephrins, where they effectively saw through the ephrins one at a time, breaking the tethers and and freeing the cells to pull apart.

Using sophisticated experiments and imaging techniques, UC Berkeley’s Groves Lab in the College of Chemistry has investigated the mechanics of ephrin-related cell repulsion. In their recent publication, they first looked at the size of the two-dimensional area of ephrin interactions that form between two cell membranes and found it to be on the scale of tens of micrometers—that’s tens of millionths of a meter. While it sounds small to us, this area is very large relative to an individual ephrin, which is only a tiny fraction of one micrometer across, which tells us there is a huge number of ephrins contacting each other between cell membranes.

The researchers also wanted to know if movement of the ephrins within this large area was needed in order for cells to ultimately pull away from each other. To answer this question, they imposed corrals of certain sizes within one of the two cell membranes to limit lateral movement of the ephrin proteins at the cell-cell interface. To illustrate, imagine observing the behavior of 100 sheep milling around on 10 acres of land, compared to observing the same 100 sheep confined within one-acre pens in groups of 10. The researchers found that if the corrals were too small, the cells became stuck during the process of severing ephrin tethers. This experiment showed that these proteins not only need to come together to form a pattern, like pixels, but that pattern also needs to be able to move around dynamically for effective communication.

The authors emphasized the need to consider 3D spatial context when studying communication between cells in the future. Taking 3D space and multiple cells into account in experiments is challenging, but new technology and creative experiments—like those underway in the Groves Lab—will help us learn more about how cells let go of their fleeting friendships.

Featured image credit: Allison Terbush.

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