BMP7 functions predominantly as a heterodimer with BMP2 or BMP4 during mammalian embryogenesis

  1. Hyung-Seok Kim
  2. Judith Neugebauer
  3. Autumn McKnite
  4. Anup Tilak
  5. Jan L Christian  Is a corresponding author
  1. University of Utah, United States
  2. Oregon Health and Sciences University, United States

Abstract

BMP7/BMP2 or BMP7/BMP4 heterodimers are more active than homodimers in vitro, but it is not known whether these heterodimers signal in vivo. To test this, we generated knock in mice carrying a mutation (Bmp7R-GFlag) that prevents proteolytic activation of the dimerized BMP7 precursor protein. This mutation eliminates the function of BMP7 homodimers and all other BMPs that normally heterodimerize with BMP7. While Bmp7 null homozygotes are live born, Bmp7R-GFlag homozygotes are embryonic lethal and have broadly reduced BMP activity. Furthermore, compound heterozygotes carrying the Bmp7R-G allele together with a null allele of Bmp2 or Bmp4 die during embryogenesis with defects in ventral body wall closure and/or the heart. Co-immunoprecipitation assays confirm that endogenous BMP4/7 heterodimers exist. Thus, BMP7 functions predominantly as a heterodimer with BMP2 or BMP4 during mammalian development, which may explain why mutations in either Bmp4 or Bmp7 lead to a similar spectrum of congenital defects in humans.

Data availability

All data generated and analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Hyung-Seok Kim

    Department of Neurobiology and Anatomy and Internal Medicine, Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Judith Neugebauer

    Department of Neurobiology and Anatomy and Internal Medicine, Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Autumn McKnite

    Department of Neurobiology and Anatomy and Internal Medicine, Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Anup Tilak

    Department of Cell and Developmental Biology, Oregon Health and Sciences University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jan L Christian

    Department of Neurobiology and Anatomy and Internal Medicine, Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, United States
    For correspondence
    jan.christian@neuro.utah.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3812-3658

Funding

National Institutes of Health (RO1HD037976)

  • Jan L Christian

National Institutes of Health (T32DK007115)

  • Judith Neugebauer

National Institutes of Health (T32HD007491)

  • Autumn McKnite

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 National Institutes of Health. All animal procedures followed protocols approved by the University of Utah Institutional Animal Care and Use Committee (protocol #17-03007).

Reviewing Editor

  1. Marianne E Bronner, California Institute of Technology, United States

Publication history

  1. Received: May 29, 2019
  2. Accepted: September 28, 2019
  3. Accepted Manuscript published: September 30, 2019 (version 1)
  4. Version of Record published: October 9, 2019 (version 2)

Copyright

© 2019, KIm 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. Hyung-Seok Kim
  2. Judith Neugebauer
  3. Autumn McKnite
  4. Anup Tilak
  5. Jan L Christian
(2019)
BMP7 functions predominantly as a heterodimer with BMP2 or BMP4 during mammalian embryogenesis
eLife 8:e48872.
https://doi.org/10.7554/eLife.48872

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