How Neurons Navigate the Brain’s Crowded Environments
Research reveals how neurons adapt their migration strategies in crowded brain tissue, with PIEZO1 playing a key role.
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In the developing brain, neurons must travel through crowded and complex environments to reach their final destinations. This migration process is essential for establishing functional brain architecture. New research now shows that neurons are capable of switching between distinct migration strategies depending on whether they are moving along a flat surface or through confined, three-dimensional (3D) tissue environments.
Researchers from Kindai University and collaborating institutions have identified a mechanosensing mechanism that enables neurons to adapt their movement based on their surroundings. Their findings were published in Cell Reports on March 25, 2025.
Different terrains, different migration modes
Neurons use the cytoskeletal protein complex actomyosin to move through the brain. Depending on the local environment, actomyosin is redistributed within the cell to create the forces necessary for movement. In two-dimensional (2D) culture systems, cerebellar granule neurons position actomyosin at the front of the cell to pull the nucleus forward. In contrast, when these cells encounter confined 3D environments, actomyosin relocates to the rear of the cell and exerts pushing forces to propel the nucleus through narrow spaces.
Actomyosin
A protein complex formed by actin filaments and myosin motor proteins. Actomyosin is responsible for generating contractile forces within cells and plays a central role in cell movement, shape and tension.
The study suggests that neurons do not rigidly follow type-specific migration strategies, but instead flexibly adjust to environmental conditions.
The role of mechanosensing and PIEZO1
Central to this adaptive process is PIEZO1, a mechanosensitive ion channel. PIEZO1 responds to mechanical stress by allowing calcium ions to flow into the cell, initiating a signaling cascade that shifts motor proteins to the cell’s rear. This repositioning facilitates movement through tight spaces, where physical constraints demand different force dynamics compared to open surfaces.
Mechanosensitive ion channel
A protein embedded in the cell membrane that opens in response to mechanical stimuli, such as pressure or stretch. This opening allows ions to flow into or out of the cell, triggering downstream cellular responses.Microfluidic device
A tool that manipulates small volumes of fluids through channels with dimensions of tens to hundreds of micrometres. In biology, microfluidics is often used to simulate the physical environments of tissues or organs.Using a combination of live imaging, microfluidic technologies and computational modeling, the researchers demonstrated that neurons lacking PIEZO1 can still migrate under unconfined conditions but fail to do so in spatially restricted environments.
Broader implications
The findings highlight a mechanosensitive migration strategy that may be relevant beyond the nervous system. Cell migration is a key feature of many biological processes, including embryonic development, immune cell trafficking and cancer metastasis. Understanding how cells sense and respond to mechanical constraints may offer insights into diverse physiological and pathological processes.
Reference: Nakazawa N, Grenci G, Kameo Y, et al. PIEZO1-dependent mode switch of neuronal migration in heterogeneous microenvironments in the developing brain. Cell Rep. 2025;44(3):115405. doi: 10.1016/j.celrep.2025.115405
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