Environmental stiffness regulates neuronal maturation via Piezo1-mediated transthyretin activity

Kreysing EM, Gautier HO, Mukherjee S, Mooslehner K, Muresan L, Haarhoff D, Zhao X, Winkel AK, Boric T, Vásquez Sepúlveda SI, Dimitracopoulos A, Gampl N, Pillai EK, Humphrey R, Káradóttir RT, Franze K

Publication Language: English

Publication Type: Journal article

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 16

Article Number: 9842

Journal Issue: 1

DOI: 10.1038/s41467-025-64810-3

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.

Authors with CRIS profile

Eva Maria Kreysing Lehrstuhl für Medizinische Physik und Mikrogewebetechnik (IMP) Sudipta Mukherjee Lehrstuhl für Medizinische Physik und Mikrogewebetechnik Tina Boric Lehrstuhl für Medizinische Physik und Mikrogewebetechnik Sebastián Ignacio Vásquez Sepúlveda Lehrstuhl für Medizinische Physik und Mikrogewebetechnik (IMP) Niklas Gampl Lehrstuhl für Medizinische Physik und Mikrogewebetechnik Kristian Franze Lehrstuhl für Medizinische Physik und Mikrogewebetechnik (IMP)

Additional Organisation(s)

Sonderforschungsbereich 1540/1 - Erforschung der Mechanik des Gehirns (EBM): Verständnis, Engineering und Nutzung mechanischer Eigenschaften und Signale in der Entwicklung, Physiologie und Pathologie des zentralen Nervensystems

Involved external institutions

University of Cambridge GB United Kingdom (GB) Makespace Cambridge Ltd GB United Kingdom (GB)

How to cite

APA:

Kreysing, E.M., Gautier, H.O., Mukherjee, S., Mooslehner, K., Muresan, L., Haarhoff, D.,... Franze, K. (2025). Environmental stiffness regulates neuronal maturation via Piezo1-mediated transthyretin activity. Nature Communications, 16(1). https://doi.org/10.1038/s41467-025-64810-3

MLA:

Kreysing, Eva Maria, et al. "Environmental stiffness regulates neuronal maturation via Piezo1-mediated transthyretin activity." Nature Communications 16.1 (2025).

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