For a long time, scientists have known that cells don’t just wander as tissues grow. They follow invisible “chemical maps.” These maps are made of signalling molecules that spread out in gradients, like the smell of food drifting through a kitchen, telling cells which way to move and where to settle.
But here’s the newer twist: cells also respond to how their surroundings feel. If the tissue is stiff, cells behave one way; if it’s soft, they behave another. It’s like how people walk differently on solid pavement compared to a bouncy trampoline.
What scientists didn’t fully understand until recently was how these two systems, chemical cues and mechanical cues, work together. Do they talk to each other? Do they reinforce one another?
Researchers from the Max-Planck-Zentrum für Physik und Medizin (MPZPM), the Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), and the University of Cambridge, have uncovered a surprising twist: the brain’s texture also helps decide which signals appear: the brain’s texture also helps decide which signals appear.
The team, led by Prof. Kristian Franze at the Max-Planck-Zentrum für Physik und Medizin, worked with Xenopus laevis (African clawed frogs), a favorite model in developmental biology. They discovered that when brain tissue becomes stiffer, cells start producing guidance molecules that weren’t there before. One striking example is Semaphorin 3A, a chemical that helps neurons navigate.
The key player here is Piezo1, a protein that acts as a mechanical force sensor. If Piezo1 levels are high, stiff tissue sparks new chemical signals. If Piezo1 is missing, the effect vanishes.
Eva Pillai, a postdoctoral researcher at EMBL and co-lead of the study, summed it up beautifully: “We didn’t expect Piezo1 to act as both a force sensor and a sculptor of the chemical landscape in the brain. It not only detects mechanical forces, but it also helps shape the chemical signals that guide how neurons grow.”
At first, scientists thought of it mainly as a sensor, a protein that lets cells ‘feel’ the stiffness of their surroundings. But new experiments show it’s more than that. Piezo1 also helps shape the environment in which neurons live.
Here’s how: when Piezo1 levels drop, the brain tissue itself becomes less stable. That’s because two crucial adhesion proteins, NCAM1 and N-cadherin, also decrease. These proteins act like glue, keeping cells tightly connected so the tissue holds its shape. Without them, the brain’s architecture softens, altering the chemical signals floating through the tissue.
Sudipta Mukherjee, co-lead of the study, put it beautifully: “Piezo1 doesn’t just help neurons sense their environment, it helps build it. By regulating adhesion proteins, Piezo1 ensures cells remain connected, keeping the tissue firm. And that stability, in turn, influences the chemical landscape that guides neurons as they grow.”
The results indicate that Piezo1 plays two important roles: as a sensor, it detects mechanical forces and converts them into cellular responses. As a modulator, it organizes the tissue’s physical properties, maintaining the brain’s structure.
For years, scientists knew about the chemical side of the story. Molecules spread through tissue in gradients, telling axons when to turn, stop, or keep going. More recently, researchers realized that the brain’s physical properties, such as tissue stiffness, also matter. What wasn’t clear was how these two systems talk to each other.
Now, an international team has found the missing link. Working with Xenopus laevis (African clawed frogs), they discovered that the stiffness of brain tissue can actually control the production of chemical guidance cues. In other words, the brain’s texture doesn’t just shape how cells move; it changes the chemical signals themselves.
The findings reveal a direct connection between mechanical forces and chemical signalling, offering new insight into how tissues form and function. It also suggests new directions for research into disease and potential treatments.
Senior author Kristian Franze said, “Our work shows that the brain’s mechanical environment is not just a backdrop, it is an active director of development.”
“It regulates cell function not only directly, but also indirectly by modulating the chemical landscape. This study may lead to a paradigm shift in how we think about chemical signals, with implications for many processes from early embryonic development to regeneration and disease.”
It’s a breakthrough that changes how we picture brain development. The brain doesn’t just grow by following chemical signals; it also listens to the feel of its surroundings. In other words, the push and pull of the tissue itself help shape the instructions that guide neurons as they build connections.
Journal Reference:
Pillai, E.K., Mukherjee, S., Gampl, N. et al. Long-range chemical signalling in vivo is regulated by mechanical signals. Nat. Mater. (2026). DOI: 10.1038/s41563-025-02463-9