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.
Highlights
Bone morphogenetic proteins (BMPs) are secreted molecules that were initially discovered as bone inducing factors and were subsequently shown to play numerous critical roles during embryogenesis (Bragdon et al, 2011)
In the hypothetical homodimer model, all BMP activity within a given cell type is generated by homodimers of class I (BMP2 or 4) and class II BMPs (BMP5, 6 or 7) that are broadly expressed in development
This hypothetical model is consistent with our finding that BMPs preferentially form heterodimers in some contexts (Neugebauer et al, 2015), and with the genetic redundancy observed among class II BMPs
Summary
Bone morphogenetic proteins (BMPs) are secreted molecules that were initially discovered as bone inducing factors and were subsequently shown to play numerous critical roles during embryogenesis (Bragdon et al, 2011). Cleavage mutant forms of BMP7 dominantly interfere with both BMP7 and BMP4 signaling when overexpressed in Xenopus (Hawley et al, 1995; Nishimatsu and Thomsen, 1998) These studies demonstrate that BMPs can heterodimerize when overexpressed, but do not address whether endogenous BMPs heterodimerize. We show that endogenous heterodimers do form in vivo, and are the predominant functional ligand in many if not all tissues of developing mouse embryos. These findings have relevance to understanding the impact of mutations in Bmp or Bmp in humans
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
