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

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...

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Autores principales: Kim, Hyung-Seok, Neugebauer, Judith, McKnite, Autumn, Tilak, Anup, Christian, Jan L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785266/
https://www.ncbi.nlm.nih.gov/pubmed/31566563
http://dx.doi.org/10.7554/eLife.48872
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author Kim, Hyung-Seok
Neugebauer, Judith
McKnite, Autumn
Tilak, Anup
Christian, Jan L
author_facet Kim, Hyung-Seok
Neugebauer, Judith
McKnite, Autumn
Tilak, Anup
Christian, Jan L
author_sort Kim, Hyung-Seok
collection PubMed
description 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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spelling pubmed-67852662019-10-10 BMP7 functions predominantly as a heterodimer with BMP2 or BMP4 during mammalian embryogenesis Kim, Hyung-Seok Neugebauer, Judith McKnite, Autumn Tilak, Anup Christian, Jan L eLife Cell Biology 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. eLife Sciences Publications, Ltd 2019-09-30 /pmc/articles/PMC6785266/ /pubmed/31566563 http://dx.doi.org/10.7554/eLife.48872 Text en © 2019, Kim et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cell Biology
Kim, Hyung-Seok
Neugebauer, Judith
McKnite, Autumn
Tilak, Anup
Christian, Jan L
BMP7 functions predominantly as a heterodimer with BMP2 or BMP4 during mammalian embryogenesis
title BMP7 functions predominantly as a heterodimer with BMP2 or BMP4 during mammalian embryogenesis
title_full BMP7 functions predominantly as a heterodimer with BMP2 or BMP4 during mammalian embryogenesis
title_fullStr BMP7 functions predominantly as a heterodimer with BMP2 or BMP4 during mammalian embryogenesis
title_full_unstemmed BMP7 functions predominantly as a heterodimer with BMP2 or BMP4 during mammalian embryogenesis
title_short BMP7 functions predominantly as a heterodimer with BMP2 or BMP4 during mammalian embryogenesis
title_sort bmp7 functions predominantly as a heterodimer with bmp2 or bmp4 during mammalian embryogenesis
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785266/
https://www.ncbi.nlm.nih.gov/pubmed/31566563
http://dx.doi.org/10.7554/eLife.48872
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