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

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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 (Bmp7^R-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, Bmp7^R-GFlag homozygotes are embryonic lethal and have broadly reduced BMP activity. Furthermore, compound heterozygotes carrying the Bmp7^R-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.

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

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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.
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.
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.
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.
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.

"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).

Copyright

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.