Droplet forming power is key for cells to attach properly

Cells attach to each other through carefully arranged molecules. A Kobe University research team has now found that the way they organize to find their proper places is similar to how grease drops self-organize in soup.

Cells that form the surface of organs stick together tightly. To do so, they connect with their neighbors on all sides through a range of different but precisely arranged adhesion molecules. If the arrangement of these structures is disturbed, organs cannot form properly and the organism dies during development. “While the role of individual adhesion molecules has been well studied, little is known about how these molecules move to the correct locations within the cell and organize themselves,” says Kobe University cell biologist TOGASHI Hideru.

Tipped off by other research, Togashi and his colleague KUNO Shuhei focused on a molecule called afadin. The team systematically tested how this molecule interacts with others and whether different parts of it are relevant for the adhesion structures to locate to their proper positions. About their approach, Kuno says, “We believe that advancing our research without being constrained by established frameworks and avoiding preconceived notions leads to new discoveries.” This is why the Kobe University team also tested whether a mode of self-organization plays a role that hasn’t been considered for this molecule so far: the way grease drops form in soup.

In the journal Cell Reports, the team now published their findings that afadin is a hub molecule. Hub molecules bind to many other molecules and structures to ensure that they come together in the right place. Moreover, it is indeed the drop-forming mechanism that lets afadin find its own location. Kuno, the study’s first author, comments: “The most dramatic aspect is the moment captured on video when molecules simultaneously dissociate from the neatly arranged cell boundaries and then coalesce to form droplets. This phenomenon demonstrates that molecules within the cell behave in a dynamic yet surprisingly orderly manner.” In that video, one can witness what afadin does if it is momentarily released from its function as a hub molecule: It quickly convenes in droplets. “I strongly encourage you to watch this video,” says Kuno.

Like many structural molecules, afadin is a protein and has multiple parts that serve different functions. The part that’s responsible for the molecule’s ability to congregate in droplets is an “intrinsically disordered region,” meaning it doesn’t have a defined shape. But that it is essential nevertheless can be seen from molecule’s inability to locate properly if this region is specifically cut out. Even more, if it is replaced by a different intrinsically disordered region from another molecule, it is able to locate to the right part of the cell again, albeit in a slightly different place. As many a professor’s office might bear testimony to, details matter even in disordered regions.

This research has implications far beyond the realm of molecular biology textbooks. Tissue formation plays a role in many fields of medical and technological relevance, such as cancer metastasis and tissue engineering. Togashi expresses his vision, saying, “By understanding the mechanisms through which cells autonomously form correct arrangements, this research could ultimately pave the way for the development of new medical technologies that control cell adhesion and enable the intentional design of tissues.”

This research was funded by the Japan Society for the Promotion of Science (grants JP19K03634, JP20H01823, JP22K19331, JP22H04926, and JP24H00188), the Japan Science and Technology Agency (grants JPMJPR1946 and JPMJSP2148), the Takeda Science Foundation, and the Iue Memorial Foundation. It was conducted in collaboration with researchers from Nikon Corporation and Tokyo Metropolitan University.

Kobe University is a national university with roots dating back to the Kobe Higher Commercial School founded in 1902. It is now one of Japan’s leading comprehensive research universities with nearly 16,000 students and nearly 1,700 faculty in 10 faculties and schools and 15 graduate schools. Combining the social and natural sciences to cultivate leaders with an interdisciplinary perspective, Kobe University creates knowledge and fosters innovation to address society’s challenges.