# Analysis of BMP Heterodimer formation and function

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $228,750

## Abstract

Bone morphogenetic proteins (BMPs) play critical roles in development, with members of the class I (BMP2 and
4) and class II (BMP5-7) BMP subfamilies being the dominant players. We have shown that class I/II
heterodimers, rather than individual homodimers, generate most of the BMP activity that is required for early
development. We generated knock-in mice carrying a mutation (Bmp7R-GFlag) that eliminates the function of all
BMPs that heterodimerize with BMP7. Unlike Bmp7 null homozygotes, which die after birth, Bmp7R-GFlag
homozygotes are embryonic lethal, have broadly reduced BMP activity and exhibit defects in multiple organs.
Furthermore, compound heterozygotes carrying the Bmp7R-GFlag allele together with a null allele of Bmp2 or Bmp4
die during embryogenesis and show defects in ventral body wall closure, eye and heart development. Thus,
BMP4/7 and BMP2/7 heterodimers play critical roles in early embryogenesis. This is important because class
I/II heterodimers have significantly higher specific activity than either homodimer. The choice of whether a given
BMP will form a homodimer or a heterodimer is made within the biosynthetic pathway. BMPs are made as
inactive precursor proteins that are cleaved to generate the active, disulfide-bonded ligand along with two
prodomain fragments. During biosynthesis the prodomain plays essential roles in guiding dimerization and
folding of the ligand. We have previously shown that BMP4 preferentially forms heterodimers with BMP7 when
co-expressed in Xenopus embryos, and that the prodomain of BMP4 is both necessary and sufficient for
heterodimer formation. In new preliminary studies, we identified a key residue within the BMP4 prodomain that
is required to generate fully functional homodimers and a second that is required for both homodimer and
heterodimer function. Humans heterozygous for either mutation have congenital birth defects. In the current
proposal, we will test the hypothesis that sequence elements within the BMP4 prodomain are required to
generate functional BMP4 homodimers, and/or functional heterodimers with class II BMPs. We will: 1) Identify
sequence elements in the BMP4 prodomain that are required for homodimer and/or heterodimer formation. We
will generate cDNAs encoding BMP4 carrying amino acid substitutions within the prodomain that are associated
with congenital defects in humans. Wild type or mutant BMP4 will be expressed alone or together with BMP7 in
Xenopus embryos. Functional and biochemical assays will be used to compare the specific activity and folding
of wild type and mutant BMP4 homodimers and heterodimers in vivo, and 2) Determine the role of BMP4
prodomain sequence elements in mammalian development. We will generate conditional knock-in mice carrying
point mutations at the Bmp4 locus that lead to amino acid substitutions within the prodomain, and that are
associated with congenital defects in humans We will perform preliminary analysis of development to collect data
that will...

## Key facts

- **NIH application ID:** 10149818
- **Project number:** 1R21HD102668-01A1
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Jan L Christian
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $228,750
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149818

## Citation

> US National Institutes of Health, RePORTER application 10149818, Analysis of BMP Heterodimer formation and function (1R21HD102668-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10149818. Licensed CC0.

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