As the brain develops, neurons grow long extensions known as axons. These structures connect different regions of the brain and transmit signals both within the brain and throughout the body. To establish these connections, axons must travel along very specific routes through brain tissue. Their journey depends on chemical signals as well as the physical characteristics of the environment around them.
Until now, scientists have not fully understood how these two types of guidance work together. An international research team has discovered that the stiffness of brain tissue can control the production of important signalling molecules. The findings, published in Nature Materials, reveal a direct link between mechanical forces and chemical signalling in the brain. This insight may also help researchers better understand how other organs develop and could eventually inspire new medical strategies.
Chemical Signals and Physical Cues Work Together
For many years, scientists have known that chemical signals guide how tissues grow and organize. Gradients of signalling molecules act like directional cues, helping cells move and develop in the correct locations.
More recent studies have shown that physical factors such as tissue stiffness also influence how cells behave. However, the relationship between these mechanical cues and chemical signals has remained unclear. Understanding how the two interact is critical for explaining how complex tissues such as the brain form during development.
Study Reveals Tissue Stiffness Controls Key Brain Signals
Researchers from the Max-Planck-Zentrum für Physik und Medizin (MPZPM), the Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), and the University of Cambridge investigated this question using Xenopus laevis (African clawed frogs), a widely used model organism in developmental biology. Their experiments showed that tissue stiffness can regulate the production of important chemical guidance cues.
This process is controlled by a mechanosensitive protein called Piezo1. The team, led by Prof. Kristian Franze, found that when tissue stiffness increased, cells began producing signalling molecules that are normally absent from those areas. One example is the guidance molecule Semaphorin 3A. Notably, this response only occurred when Piezo1 levels were sufficiently high.
“We didn’t expect Piezo1 to act as both a force sensor and a sculptor of the chemical landscape in the brain,” said study co-lead Eva Pillai, a postdoctoral researcher at the European Molecular Biology Laboratory (EMBL). “It not only detects mechanical forces — it helps shape the chemical signals that guide how neurons grow. This kind of connection between the brain’s physical and chemical worlds gives us a whole new way of thinking about how it develops.”
Piezo1 Also Helps Maintain Tissue Structure
The researchers also discovered that Piezo1 influences the physical stability of brain tissue itself. When the amount of Piezo1 is reduced, levels of important cell adhesion proteins including NCAM1 and N-cadherin drop. These proteins are crucial for maintaining cell-cell contacts — which glue cells together.
“What’s exciting is that Piezo1 doesn’t just help neurons sense their environment — it helps build it,” said Sudipta Mukherjee, study co-lead and postdoctoral researcher at FAU and MPZPM. He and Pillai were both doctoral students at the University of Cambridge, where the project was initiated. “By regulating the levels of these adhesion proteins, Piezo1 keeps cells well connected, which is essential for a stable tissue architecture. The stability of the enviroment in turn, influences the chemical environment.”
The results indicate that Piezo1 performs two important roles. It acts as a sensor that converts mechanical signals from the surrounding environment into cellular responses. At the same time, it functions as a modulator that helps organize the mechanical properties of the tissue itself.
Implications for Development and Disease
These findings could have wide ranging significance for developmental biology and medical research. Errors in neuron growth are associated with congenital and neurodevelopmental disorders. In addition, tissue stiffness has been linked to diseases such as cancer.
By demonstrating that mechanical forces can shape chemical signalling, the study provides new insight into how tissues form and function. It also suggests new directions for research into disease and potential treatments.
“Our work shows that the brain’s mechanical environment is not just a backdrop — it is an active director of development,” said senior author Kristian Franze. “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.”
The researchers also found that tissue stiffness can influence chemical signalling across long distances, affecting the behavior of cells far from where the mechanical force originates. Overall, the study highlights mechanical forces as a powerful regulator of development and organ function.
