# The role of BMP signaling in craniofacial cartilage development

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $365,750

## Abstract

PROJECT SUMMARY
Craniofacial abnormalities are largely attributed to defects in the formation, migration and differentiation of
cranial neural crest cells (CNCCs). Since CNCCs are developmentally plastic, understanding the genetic and
molecular pathways controlling the specification of chondrocyte and osteoblast lineages from CNCC is a
prerequisite for interpreting the etiology of craniofacial skeletal disorders. After the discovery of bone
morphogenetic proteins (BMPs), many elegant studies have revealed their significant role in skeletal
development. However, it is still unclear why BMPs are capable of changing the fate and lineage of
undifferentiated stem cells of CNCCs toward skeletogenic cells. Especially, despite the importance of BMPs
during craniofacial bone development, it is poorly understood how BMP signaling in CNCCs regulates
craniofacial cartilage formation.
 In our preliminary studies, we employed the Cre-LoxP system that controls BMP signaling in a BMP
receptor-specific manner in the mouse. It has been reported that gain-of-function mutations in components of
the BMP axis cause craniofacial abnormalities in humans. Consistent with this observation, we previously
reported that augmentation of BMP signaling in CNCCs through BMPR1A, one of the BMP type I receptors,
causes craniosynostosis due to ectopic cartilage formation in cranial sutures. In this proposal, we focus on
another BMP type I receptor, ACVR1. Embryos with augmented BMP signaling through ACVR1 in CNCCs
(“ACVR1 mutants” hereafter) displayed jaw malformation and cleft lip, which are distinct craniofacial
phenotypes from those of BMPR1A mutants. Interestingly, ACVR1 mutants displayed the enhanced cartilage
growth in the face with upregulation of Sox9, a key transcription factor for chondrogenesis. Preliminary
screenings revealed that the levels of mammalian target of rapamycin (mTOR) were significantly elevated in
ACVR1 mutants. Importantly, inhibition of mTOR signaling by rapamycin rescued the craniofacial cartilage
malformation in ACVR1 mutants, indicating that mTOR signaling triggered by the augmentation of BMP is
responsible for the enhanced endochondral ossification. Of note, primary cilia, which are microtubule-based
antenna-like organelles, were enriched in CNCC-derived chondrocytes in ACVR1 mutants, and the
suppression of a ciliary protein rescued the craniofacial cartilage abnormalities in ACVR1 mutants. These
results suggest that primary cilia in ACVR1 mutants are responsible for the etiology of enhanced cartilage
growth in the face. Our central hypothesis here is that BMP signaling through ACVR1 in CNCCs regulates
mTOR, which is required for primary cilium formation during craniofacial cartilage development. We will test
our hypothesis by pursuing the specific aims (1) To examine how BMP signaling in CNCCs regulates primary
cilium formation during chondrogenesis, and (2) To examine how BMP-mTOR-cilia axis governs
chondrogenesis during facial development.
 Our st...

## Key facts

- **NIH application ID:** 9892877
- **Project number:** 5R01DE025897-04
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Yoshihiro Komatsu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $365,750
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9892877

## Citation

> US National Institutes of Health, RePORTER application 9892877, The role of BMP signaling in craniofacial cartilage development (5R01DE025897-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9892877. Licensed CC0.

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