Dephosphorylation of the NPR2 guanylyl cyclase contributes to inhibition of bone growth by fibroblast growth factor

  1. Leia C Shuhaibar  Is a corresponding author
  2. Jerid W Robinson
  3. Giulia Vigone
  4. Ninna P Shuhaibar
  5. Jeremy R Egbert
  6. Valentina Baena
  7. Tracy F Uliasz
  8. Deborah Kaback
  9. Siu-Pok Yee
  10. Robert Feil
  11. Melanie C Fisher
  12. Caroline N Dealy
  13. Lincoln R Potter  Is a corresponding author
  14. Laurinda A Jaffe  Is a corresponding author
  1. University of Connecticut Health Center, United States
  2. University of Minnesota, United States
  3. University of Tübingen, Germany

Abstract

Activating mutations in fibroblast growth factor (FGF) receptor 3 and inactivating mutations in the NPR2 guanylyl cyclase both cause severe short stature, but how these two signaling systems interact to regulate bone growth is poorly understood. Here, we show that bone elongation is increased when NPR2 cannot be dephosphorylated and thus produces more cyclic GMP. By developing an in vivo imaging system to measure cyclic GMP production in intact tibia, we show that FGF-induced dephosphorylation of NPR2 decreases its guanylyl cyclase activity in growth plate chondrocytes in living bone. Thus FGF signaling lowers cyclic GMP production in the growth plate, which counteracts bone elongation. These results define a new component of the signaling network by which activating mutations in the FGF receptor inhibit bone growth.

Article and author information

Author details

  1. Leia C Shuhaibar

    Department of Cell Biology, University of Connecticut Health Center, Farmington, United States
    For correspondence
    shuhaibar@uchc.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Jerid W Robinson

    Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Giulia Vigone

    Department of Cell Biology, University of Connecticut Health Center, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ninna P Shuhaibar

    Department of Cell Biology, University of Connecticut Health Center, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jeremy R Egbert

    Department of Cell Biology, University of Connecticut Health Center, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Valentina Baena

    Department of Cell Biology, University of Connecticut Health Center, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Tracy F Uliasz

    Department of Cell Biology, University of Connecticut Health Center, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Deborah Kaback

    Department of Cell Biology, University of Connecticut Health Center, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Siu-Pok Yee

    Department of Cell Biology, University of Connecticut Health Center, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Robert Feil

    Department of Biochemistry, University of Tübingen, Tübingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Melanie C Fisher

    Center for Regenerative Medicine and Skeletal Development, University of Connecticut Health Center, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Caroline N Dealy

    Center for Regenerative Medicine and Skeletal Development, University of Connecticut Health Center, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Lincoln R Potter

    Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, United States
    For correspondence
    potter@umn.edu
    Competing interests
    The authors declare that no competing interests exist.
  14. Laurinda A Jaffe

    Department of Cell Biology, University of Connecticut Health Center, Farmington, United States
    For correspondence
    ljaffe@uchc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2636-5721

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R37HD014939)

  • Laurinda A Jaffe

National Institute of General Medical Sciences (R01GM098309)

  • Lincoln R Potter

National Institute of Diabetes and Digestive and Kidney Diseases (Postdoctoral training grant:T32DK007203)

  • Jerid W Robinson

National Institute of Dental and Craniofacial Research (Postdoctoral training grant:R90DE022526)

  • Ninna P Shuhaibar

Fund for Science (Postdoctoral scholarship (mentor)))

  • Laurinda A Jaffe

Fund for Science (Postdoctoral scholarship (postdoc)))

  • Leia C Shuhaibar

Fund for Science (Research grant)

  • Caroline N Dealy

Fund for Science (Research grant)

  • Lincoln R Potter

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were conducted as approved by the animal care committees of the University of Connecticut Health Center (101395-0519) and the University of Minnesota (1507-32769A).

Reviewing Editor

  1. Gail Mandel, Oregon Health & Science University, United States

Publication history

  1. Received: September 22, 2017
  2. Accepted: December 2, 2017
  3. Accepted Manuscript published: December 4, 2017 (version 1)
  4. Version of Record published: December 27, 2017 (version 2)

Copyright

© 2017, Shuhaibar 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.

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  1. Leia C Shuhaibar
  2. Jerid W Robinson
  3. Giulia Vigone
  4. Ninna P Shuhaibar
  5. Jeremy R Egbert
  6. Valentina Baena
  7. Tracy F Uliasz
  8. Deborah Kaback
  9. Siu-Pok Yee
  10. Robert Feil
  11. Melanie C Fisher
  12. Caroline N Dealy
  13. Lincoln R Potter
  14. Laurinda A Jaffe
(2017)
Dephosphorylation of the NPR2 guanylyl cyclase contributes to inhibition of bone growth by fibroblast growth factor
eLife 6:e31343.
https://doi.org/10.7554/eLife.31343

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