During the development of the brain, neurons extend long processes called “axons” through a crowded environment along well-defined pathways to connect to distant cells. These connections eventually give rise to highly complex neuronal networks, along which information is transmitted and processed throughout the body. Past research has identified a variety of small signalling molecules that cells in the brain secrete to tell developing neurons where to grow. However, these molecules alone cannot explain the complex neuronal growth patterns we see.
We previously showed that neurons also respond to mechanical cues, such as local tissue stiffness, suggesting that mechanical signals are likely an important missing part of the puzzle. However, how neurons feel tissue stiffness, and how mechanical (tissue stiffness) and chemical (small signalling molecules) signals work together to guide growing neurons during development is currently unknown. As defects in axon guidance can lead to a variety of so-called neurodevelopmental disorders, understanding how neuronal growth is regulated is crucial not only for our understanding of brain development but also for illuminating new facets of human diseases.
This project aimed to close this comprehension gap. By developing and combining state-of-the-art approaches in physics, engineering and biology, we investigated mechanosensitive molecular mechanisms that regulate neuronal growth and guidance. In particular, we developed new methods that allowed us to investigate how tissue stiffness impacts neuronal growth directly (through regulation of the forces exerted by neurons on their environment) and indirectly (by modulating chemical signalling pathways). Furthermore, we developed a mathematical model based on our findings, which illuminated the role of stiffness gradients in guiding axons through developing brain tissue.
We identified an intense cross-talk between chemical and mechanical signals. Changes in tissue stiffness led to changes in the chemical landscape in the developing brain and vice versa. Also, the way in which neurons responded to certain chemical signals was regulated by tissue stiffness. We identified molecular signalling pathways enabling neurons to integrate mechanical and chemical signals and confirmed their cross-talk in an in vivo system. Hence, our project unveiled new mechanisms of axon guidance with importance to brain development and potentially disease. The integration of mechanical and chemical signals by neurons identified here is likely also taking place in many other cell types, tissues and organ systems, thus opening many new avenues of future research.
