1. Developmental Biology
Download icon

Piezo1/2 mediate mechanotransduction essential for bone formation through concerted activation of NFAT-YAP1-β-catenin

  1. Taifeng Zhou
  2. Bo Gao
  3. Yi Fan
  4. Yuchen Liu
  5. Shuhao Feng
  6. Qian Cong
  7. Xiaolei Zhang
  8. Yaxing Zhou
  9. Prem S Yadav
  10. Jiachen Lin
  11. Nan Wu
  12. Liang Zhao
  13. Dongsheng Huang
  14. Shuanhu Zhou
  15. Peiqiang Su  Is a corresponding author
  16. Yingzi Yang  Is a corresponding author
  1. Harvard School of Dental Medicine, United States
  2. Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, China
  3. Nanfang Hospital, Southern Medical University, China
  4. Sun Yat-sen Memorial Hospital, Sun Yat-sen University, China
  5. Brigham and Women's Hospital, United States
  6. First Affiliated Hospital of Sun Yat-sen University, China
Research Article
  • Cited 8
  • Views 3,962
  • Annotations
Cite this article as: eLife 2020;9:e52779 doi: 10.7554/eLife.52779

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.

Article and author information

Author details

  1. Taifeng Zhou

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Bo Gao

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Yi Fan

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Yuchen Liu

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Shuhao Feng

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Qian Cong

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Xiaolei Zhang

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Yaxing Zhou

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Prem S Yadav

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Jiachen Lin

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Nan Wu

    Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9429-2889

  12. Liang Zhao

    Department of Orthopedic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  13. Dongsheng Huang

    Department of Spine Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  14. Shuanhu Zhou

    Department of Orthopedic Surgery, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  15. Peiqiang Su

    Department of Orthopaedic Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
    For correspondence
    supq@mail.sysu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.

  16. Yingzi Yang

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    For correspondence
    yingzi_yang@hsdm.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3933-887X

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.

Reviewing Editor

  1. Mone Zaidi, Icahn School of Medicine at Mount Sinai, United States

Publication history

  1. Received: October 16, 2019
  2. Accepted: March 17, 2020
  3. Accepted Manuscript published: March 18, 2020 (version 1)
  4. 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

  • 3,962
    Page views
  • 796
    Downloads
  • 8
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Categories and tags

Research organism

Further reading

    1. Cell Biology
    2. Developmental Biology

    A Non-stop identity complex (NIC) supervises enterocyte identity and protects from premature aging

    Neta Erez et al.
    Research Article Updated

    A hallmark of aging is loss of differentiated cell identity. Aged Drosophila midgut differentiated enterocytes (ECs) lose their identity, impairing tissue homeostasis. To discover identity regulators, we performed an RNAi screen targeting ubiquitin-related genes in ECs. Seventeen genes were identified, including the deubiquitinase Non-stop (CG4166). Lineage tracing established that acute loss of Non-stop in young ECs phenocopies aged ECs at cellular and tissue levels. Proteomic analysis unveiled that Non-stop maintains identity as part of a Non-stop identity complex (NIC) containing E(y)2, Sgf11, Cp190, (Mod) mdg4, and Nup98. Non-stop ensured chromatin accessibility, maintaining the EC-gene signature, and protected NIC subunit stability. Upon aging, the levels of Non-stop and NIC subunits declined, distorting the unique organization of the EC nucleus. Maintaining youthful levels of Non-stop in wildtype aged ECs safeguards NIC subunits, nuclear organization, and suppressed aging phenotypes. Thus, Non-stop and NIC, supervise EC identity and protects from premature aging.

    1. Developmental Biology

    Deficient spermiogenesis in mice lacking Rlim

    Feng Wang et al.
    Research Article Updated

    The X-linked gene Rlim plays major roles in female mouse development and reproduction, where it is crucial for the maintenance of imprinted X chromosome inactivation in extraembryonic tissues of embryos. However, while females carrying a systemic Rlim knockout (KO) die around implantation, male Rlim KO mice appear healthy and are fertile. Here, we report an important role for Rlim in testis where it is highly expressed in post-meiotic round spermatids as well as in Sertoli cells. Systemic deletion of the Rlim gene results in lower numbers of mature sperm that contains excess cytoplasm, leading to decreased sperm motility and in vitro fertilization rates. Targeting the conditional Rlim cKO specifically to the spermatogenic cell lineage largely recapitulates this phenotype. These results reveal functions of Rlim in male reproduction specifically in round spermatids during spermiogenesis.

    1. Developmental Biology
    2. Neuroscience

    Glial insulin regulates cooperative or antagonistic Golden goal/Flamingo interactions during photoreceptor axon guidance

    Hiroki Takechi et al.
    Research Article

    Transmembrane protein Golden goal (Gogo) interacts with atypical cadherin Flamingo to direct R8 photoreceptor axons in the Drosophila visual system. However, the precise mechanisms underlying Gogo regulation during columnar- and layer-specific R8 axon targeting are unknown. Our studies demonstrated that the insulin secreted from surface and cortex glia switches the phosphorylation status of Gogo, thereby regulating its two distinct functions. Non-phosphorylated Gogo mediates the initial recognition of the glial protrusion in the center of the medulla column, whereas phosphorylated Gogo suppresses radial filopodia extension by counteracting Flamingo to maintain a one axon to one column ratio. Later, Gogo expression ceases during the midpupal stage, thus allowing R8 filopodia to extend vertically into the M3 layer. These results demonstrate that the long- and short-range signaling between the glia and R8 axon growth cones regulates growth cone dynamics in a stepwise manner, and thus shape the entire organization of the visual system.