Piezo1/2 mediate mechanotransduction essential for bone formation through concerted activation of NFAT-YAP1-β-catenin
- Harvard School of Dental Medicine, United States
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, China
- Nanfang Hospital, Southern Medical University, China
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, China
- Brigham and Women's Hospital, United States
- First Affiliated Hospital of Sun Yat-sen University, China
Abstract
Mechanical forces are fundamental regulators of cell behaviors. However, molecular regulation of mechanotransduction remain poorly understood. Here we identified the mechanosensitive channels Piezo1 and Piezo2 as key force sensors required for bone development and osteoblast differentiation. Loss of Piezo1, or more severely Piezo1/2, in mesenchymal or osteoblast progenitor cells, led to multiple spontaneous bone fractures in newborn mice due to inhibition of osteoblast differentiation and increased bone resorption. In addition, loss of Piezo1/2 rendered resistant to further bone loss caused by unloading in both bone development and homeostasis. Mechanistically, Piezo1/2 relayed fluid shear stress and extracellular matrix stiffness signals to activate Ca2+ influx to stimulate Calcineurin, which promotes concerted activation of NFATc1, YAP1 and β-catenin transcription factors by inducing their dephosphorylation as well as NFAT/YAP1/β-catenin complex formation. Yap1 and β-catenin activities were reduced in the Piezo1 and Piezo1/2 mutant bones and such defects were partially rescued by enhanced β-catenin activities.
Data availability
RNAseq source data for Figure. S3 has been deposited in GEO under the accession number GSE139121.All data generated or analysed during this study are included in the manuscript and supporting files.
-
RNA seq of femur and humerus bone tissues from Prx1cre driven Piezo1/2 mutant pups at the age of P0NCBI Gene Expression Omnibus, GSE139121.
Article and author information
Author details
Funding
National Institute of Dental and Craniofacial Research (R01DE025866)
- Yingzi Yang
National Institute of Dental and Craniofacial Research (R01DE025866)
- Qian Cong
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR070877)
- Yingzi Yang
National Cancer Institute (R01CA222571)
- Yuchen Liu
China Scholarship Council (201806380049)
- Taifeng Zhou
China Scholarship Council (201806210436)
- Jiachen Lin
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR070877)
- Prem S Yadav
National Institute of Arthritis and Musculoskeletal and Skin Diseases
- Yi Fan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Mone Zaidi, Icahn School of Medicine at Mount Sinai, United States
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the NIH. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#IS00000121-3) of the Harvard Medical School. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Harvard Medical School.
Version history
- Received: October 16, 2019
- Accepted: March 17, 2020
- Accepted Manuscript published: March 18, 2020 (version 1)
- Version of Record published: April 1, 2020 (version 2)
Copyright
© 2020, Zhou et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 9,827
- views
-
- 1,740
- downloads
-
- 190
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Piezo1/2 mediate mechanotransduction essential for bone formation through concerted activation of NFAT-YAP1-β-catenin
eLife 9:e52779.
https://doi.org/10.7554/eLife.52779
Further reading
-
- Developmental Biology
Precise developmental timing control is essential for organism formation and function, but its mechanisms are unclear. In C. elegans, the microRNA lin-4 critically regulates developmental timing by post-transcriptionally downregulating the larval-stage-fate controller LIN-14. However, the mechanisms triggering the activation of lin-4 expression toward the end of the first larval stage remain unknown. We demonstrate that the transmembrane transcription factor MYRF-1 is necessary for lin-4 activation. MYRF-1 is initially localized on the cell membrane, and its increased cleavage and nuclear accumulation coincide with lin-4 expression timing. MYRF-1 regulates lin-4 expression cell-autonomously and hyperactive MYRF-1 can prematurely drive lin-4 expression in embryos and young first-stage larvae. The tandem lin-4 promoter DNA recruits MYRF-1GFP to form visible loci in the nucleus, suggesting that MYRF-1 directly binds to the lin-4 promoter. Our findings identify a crucial link in understanding developmental timing regulation and establish MYRF-1 as a key regulator of lin-4 expression.
-
- Developmental Biology
- Structural Biology and Molecular Biophysics
The receptor tyrosine kinase ROR2 mediates noncanonical WNT5A signaling to orchestrate tissue morphogenetic processes, and dysfunction of the pathway causes Robinow syndrome, brachydactyly B, and metastatic diseases. The domain(s) and mechanisms required for ROR2 function, however, remain unclear. We solved the crystal structure of the extracellular cysteine-rich (CRD) and Kringle (Kr) domains of ROR2 and found that, unlike other CRDs, the ROR2 CRD lacks the signature hydrophobic pocket that binds lipids/lipid-modified proteins, such as WNTs, suggesting a novel mechanism of ligand reception. Functionally, we showed that the ROR2 CRD, but not other domains, is required and minimally sufficient to promote WNT5A signaling, and Robinow mutations in the CRD and the adjacent Kr impair ROR2 secretion and function. Moreover, using function-activating and -perturbing antibodies against the Frizzled (FZ) family of WNT receptors, we demonstrate the involvement of FZ in WNT5A-ROR signaling. Thus, ROR2 acts via its CRD to potentiate the function of a receptor super-complex that includes FZ to transduce WNT5A signals.
