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.
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.
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
-
- 10,881
- views
-
- 1,875
- downloads
-
- 236
- 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
Correct intestinal morphogenesis depends on the early embryonic process of gut rotation, an evolutionarily conserved program in which a straight gut tube elongates and forms into its first loops. However, the gut tube requires guidance to loop in a reproducible manner. The dorsal mesentery (DM) connects the gut tube to the body and directs the lengthening gut into stereotypical loops via left-right (LR) asymmetric cellular and extracellular behavior. The LR asymmetry of the DM also governs blood and lymphatic vessel formation for the digestive tract, which is essential for prenatal organ development and postnatal vital functions including nutrient absorption. Although the genetic LR asymmetry of the DM has been extensively studied, a divider between the left and right DM has yet to be identified. Setting up LR asymmetry for the entire body requires a Lefty1+ midline barrier to separate the two sides of the embryo, without it, embryos have lethal or congenital LR patterning defects. Individual organs including the brain, heart, and gut also have LR asymmetry, and while the consequences of left and right signals mixing are severe or even lethal, organ-specific mechanisms for separating these signals remain poorly understood. Here, we uncover a midline structure composed of a transient double basement membrane, which separates the left and right halves of the embryonic chick DM during the establishment of intestinal and vascular asymmetries. Unlike other basement membranes of the DM, the midline is resistant to disruption by intercalation of Netrin4 (Ntn4). We propose that this atypical midline forms the boundary between left and right sides and functions as a barrier necessary to establish and protect organ asymmetry.
-
- Developmental Biology
Numerous reports showed that the epididymis plays key roles in the acquisition of sperm fertilizing ability but its contribution to embryo development remains less understood. Female mice mated with males with simultaneous mutations in Crisp1 and Crisp3 genes exhibited normal in vivo fertilization but impaired embryo development. In this work, we found that this phenotype was not due to delayed fertilization, and it was observed in eggs fertilized by epididymal sperm either in vivo or in vitro. Of note, eggs fertilized in vitro by mutant sperm displayed impaired meiotic resumption unrelated to Ca2+ oscillations defects during egg activation, supporting potential sperm DNA defects. Interestingly, cauda but not caput epididymal mutant sperm exhibited increased DNA fragmentation, revealing that DNA integrity defects appear during epididymal transit. Moreover, exposing control sperm to mutant epididymal fluid or to Ca2+-supplemented control fluid significantly increased DNA fragmentation. This, together with the higher intracellular Ca2+ levels detected in mutant sperm, supports a dysregulation in Ca2+ homeostasis within the epididymis and sperm as the main factor responsible for embryo development failure. These findings highlight the contribution of the epididymis beyond fertilization and identify CRISP1 and CRISP3 as novel factors essential for sperm DNA integrity and early embryo development.
