# Analysis of BMP Heterodimer Formation and Function

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $67,692

## Abstract

Project Summary
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 collec...

## Key facts

- **NIH application ID:** 10406484
- **Project number:** 3R21HD102668-01A1S1
- **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:** $67,692
- **Award type:** 3
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10406484

## Citation

> US National Institutes of Health, RePORTER application 10406484, Analysis of BMP Heterodimer Formation and Function (3R21HD102668-01A1S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10406484. Licensed CC0.

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