Foxc1 controls the growth of the murine frontal bone rudiment by direct regulation of a Bmp response threshold of Msx2
Open accessAbstract
The mammalian skull vault consists of several intricately patterned bones that grow in close coordination. The growth of these bones depends on the precise regulation of the migration and differentiation of osteogenic cells from undifferentiated precursor cells located above the eye. Here, we demonstrate a role for Foxc1 in modulating the influence of Bmp signaling on the expression of Msx2 and the specification of these cells. Inactivation of Foxc1 results in a dramatic reduction in skull vault growth and causes an expansion of Msx2 expression and Bmp signaling into the area occupied by undifferentiated precursor cells. Foxc1 interacts directly with a Bmp responsive element in an enhancer upstream of Msx2, and acts to reduce the occupancy of P-Smad1/5/8. We propose that Foxc1 sets a threshold for the Bmp-dependent activation of Msx2, thus controlling the differentiation of osteogenic precursor cells and the rate and pattern of calvarial bone development.
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Msx2 expression responds to BMP2/4, and further activates canonical Wnt signaling in osteoblast progenitors.
“Mechanistically, Msx2 expression responds to BMP2/4, and further activates canonical Wnt signaling in osteoblast progenitors49,50.”
From Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis (2025) · cites this paper as [50]
The Results (page unavailable) show that BMP2-soaked beads increased Msx2 expression, and expanded Bmp2/Bmp4 expression coincided with an expanded Msx2 domain. The paper does not report that Msx2 activates canonical Wnt signaling in osteoblast progenitors; its Results mention Wnt1-Cre only as a lineage-tracing tool. (LLM, conf=0.88)
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“Mechanistically, Msx2 expression responds to BMP2/4, and further activates canonical Wnt signaling in osteoblast progenitors 49,50 .”
- Authors
- Sun, J., Ishii, M., Ting, M.-C., & Maxson, R.
- Affiliations
- University of Southern California (US)
- Corresponding author
- Maxson, Robert
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2013-03-01
- Volume
- 140
- Issue
- 5
- Pages
- 1034-1044
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- PMC
- PMC3583041
- OpenAlex
- W1994675789
- Cited by
- 57
- References
- 54
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 1 · 2022: 5 · 2021: 7 · 2020: 5 · 2019: 5 · 2018: 7 · 2017: 5 · 2016: 3 · 2015: 7 · 2014: 3 · 2013: 1
- FWCI
- 3.09
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Dental and Craniofacial Research (R01DE016320, R01DE019650)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Craniofacial Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- FOXC1, Msx2, BMP signaling, frontal bone, Smad1/5/8 phosphorylation, enhancer regulation, transcriptional regulation, osteogenic differentiation
- MeSH terms
- Animals, Bone Development, Cell Differentiation, Cells, Cultured, Embryo, Mammalian, Frontal Bone, Mice, Inbred C57BL, Mice, Transgenic, Osteogenesis, Skull, Homeodomain Proteins, Gene Expression Regulation, Developmental, Bone Morphogenetic Proteins, Mice, Forkhead Transcription Factors, Bone Morphogenetic Protein 2, Bone Morphogenetic Protein 4
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