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

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 (<i>Bmp7^R-GFlag</i>) 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 <i>Bmp7</i> null homozygotes are live born, <i>Bmp7^R-GFlag</i> homozygotes are embryonic lethal and have broadly reduced BMP activity. Furthermore, compound heterozygotes carrying the <i>Bmp7^R-G</i> allele together with a null allele of <i>Bmp2</i> or <i>Bmp4</i> 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 <i>Bmp4</i> or <i>Bmp7</i> lead to a similar spectrum of congenital defects in humans.