Mechanics paves the way for nerve cells

By tracking real-time changes in physical properties of the embryonic brain, researchers from the Franze lab have shown that changes in brain stiffness tell growing nerve cells which way to turn

As the embryonic brain wires up, it prepares the region just in front of where developing nerve cells need to grow in order to arrive at the right place.

Researchers have found that the developing brain lays down mechanical paths for nerve cells, which can ‘feel’ their physical environment as they grow. The study, published by the Franze lab in the journal eLife, sheds new light on how the physical environment helps shape crucial processes in brain development. The scientists found that local brain stiffness changed remarkably quickly and these changes were instructive, telling nerve cells where to grow. They also found that local brain stiffness was controlled by where cells divided and how closely they were then packed together in the underlying tissue.

During development, nerve cells send out long protrusions, called axons, which wire up different parts of the brain, much like telegraph cables help us to communicate across long distances. To do this, axons need to grow along complex routes to get to their final destination. Errors in this process during early development can result in severe neurological disorders.

Scientists have known for decades that chemical signals play an important role in guiding axons, allowing them to ‘sniff’ out where they need to go. More recent research has shown that axons can also ‘feel’ and respond to the stiffness of their environment. Previous work from the Franze lab showed that the developing brain contains a stiffness gradient that axons follow. In this eLife study, the researchers wanted to find out when the stiffness gradient appeared, how it changed over time, and whether it actively guided the axons to turn.

To draw a direct link between axon guidance and brain stiffness, the authors developed a new method to image the axons as they grew across the brain, while simultaneously measuring the rapidly evolving stiffness of brain tissue in the same area. Using this method, which they called timelapse in vivo AFM (tiv-AFM), they could pinpoint when the stiffness gradient first emerged and track it across a time scale of minutes. The stiffness gradient appeared just before the axons grew in that area and, crucially, before they turned. Amelia Thompson and Eva Pillai, the lead authors of this study, said that “the future applications of tiv-AFM are very exciting, there has been a lot of interest in using our method to answer different scientific questions in a variety of model systems”.

This study also showed that changes in local cell density contribute substantially to the developing stiffness gradient. Stiffer areas had more cells while softer areas had fewer cells. When brains were treated with a drug to stop cell numbers from increasing, both the stiffness gradient and axon turning were greatly decreased. These results establish a causal link between biological structures in the brain, their contribution to mechanics, and in turn their involvement in axon growth and guidance. In other words, mechanics are important to ensure correct wiring of the developing brain.

Kristian Franze, the research group leader, said that “it was really surprising to us how quickly and reproducibly tissue stiffness changed, and how important this was for neurons to grow along the proper path”. Ultimately, the researchers hope that a better understanding of the relationship between cell behaviour and environmental stiffness could inspire better therapeutic strategies to help regrow damaged nerve cells after brain or spinal cord injury.

Reference: Amelia J Thompson, Eva K Pillai, Ivan B Dimov, Sarah K Foster, Christine E Holt, Kristian Franze, Rapid changes in tissue mechanics regulate cell behaviour in the developing embryonic brain, eLife 2019;8:e39356 doi: 10.7554/eLife.39356