Environmental stiffness regulates neuronal maturation via Piezo1-mediated transthyretin activity
Year: 2025
Type: article
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.
Source: Nature Communications
Authors: 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, Kristian Franze
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Alexander von Humboldt-Stiftung, Wellcome Trust, Research Councils UK, Deutsche Forschungsgemeinschaft, Cambridge Trust, Medical Research Council, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, HORIZON EUROPE European Research Council
Awards: G2143627703, The mechanical regulation of chemical signaling in axon pathfinding in the developing Xenopus laevis brain, G3775157028, Computational microscopy in Cambridge Advanced Imaging Centre, The mechanical control of neuronal maturation, Bio-image processing at exascale, G486966024, G5188208403, The mechanical regulation of chemical signaling in axon pathfinding in the developing Xenopus laevis brain, GRK 2162: Entwicklung und Vulnerabilität des Zentralnervensystems, SFB 1540: Erforschung der Mechanik des Gehirns (EBM):
Verständnis, Engineering und Nutzung mechanischer Eigenschaften und Signale in der Entwicklung, Physiologie und Pathologie des zentralen Nervensystems, Unfolding the dynamic interplay of mechanical and molecular processes in brain folding, Functional implications of focal white matter lesions on neuronal circuits, G8995168184
OpenAlex ID: W4415989552