Environmental stiffness regulates neuronal maturation via Piezo1-mediated transthyretin activity

Eva Kreysing (), Hélène O. B. Gautier, Sudipta Mukherjee, Katrin A. Mooslehner, Leila Muresan, Daniel Haarhoff, Xiaohui Zhao, Alexander K. Winkel, Tina Borić, Sebastián Vásquez-Sepúlveda, Niklas Gampl, Andrea Dimitracopoulos, Eva K. Pillai, Robert Humphrey, Ragnhildur Thóra Káradóttir () and Kristian Franze ()
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Eva Kreysing: University of Cambridge
Hélène O. B. Gautier: University of Cambridge
Sudipta Mukherjee: University of Cambridge
Katrin A. Mooslehner: University of Cambridge
Leila Muresan: University of Cambridge
Daniel Haarhoff: Makespace Cambridge Ltd
Xiaohui Zhao: Heart and Lung Research Institute
Alexander K. Winkel: University of Cambridge
Tina Borić: Friedrich-Alexander-Universität Erlangen-Nürnberg
Sebastián Vásquez-Sepúlveda: Friedrich-Alexander-Universität Erlangen-Nürnberg
Niklas Gampl: Friedrich-Alexander-Universität Erlangen-Nürnberg
Andrea Dimitracopoulos: University of Cambridge
Eva K. Pillai: University of Cambridge
Robert Humphrey: University of Cambridge
Ragnhildur Thóra Káradóttir: University of Cambridge Biomedical Campus
Kristian Franze: University of Cambridge

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract During development, neurons initiate a maturation process during which they start expressing voltage-gated ion channels, form synapses, and start communicating via action potentials. Little is known about external factors regulating this process. Here, we identify environmental mechanics as an important regulator of neuronal maturation, and a molecular pathway linking tissue stiffness to this process. Using patch clamp electrophysiology, calcium imaging and immunofluorescence, we find that, in stiffer environments, neurons show a delay in voltage-gated ion channel activity, action potentials, and synapse formation. RNA sequencing and CRISPR/Cas9 knockdown reveal that the mechanosensitive ion channel Piezo1 supresses transthyretin expression on stiffer substrates, slowing down electrical maturation. In Xenopus laevis embryos, brain stiffness negatively correlates with synapse density, and artificial tissue stiffening delays synaptic activity in vivo. Our data indicate that environmental stiffness represents a fundamental regulator of neuronal maturation, critical for brain circuit development and potentially for neurodevelopmental disorders.

Date: 2025
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DOI: 10.1038/s41467-025-64810-3

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