Cell mixing at a neural crest-mesoderm boundary and deficient ephrin-Eph signaling in the pathogenesis of craniosynostosis
Open accessAbstract
Boundaries between cellular compartments often serve as signaling interfaces during embryogenesis. The coronal suture is a major growth center of the skull vault and develops at a boundary between cells derived from neural crest and mesodermal origin, forming the frontal and parietal bones, respectively. Premature fusion of these bones, termed coronal synostosis, is a common human developmental anomaly. Known causes of coronal synostosis include haploinsufficiency of TWIST1 and a gain of function mutation in MSX2. In Twist1(+/-) mice with coronal synostosis, we found that the frontal-parietal boundary is defective. Specifically, neural crest cells invade the undifferentiated mesoderm of the Twist1(+/-) mutant coronal suture. This boundary defect is accompanied by an expansion in Msx2 expression and reduction in ephrin-A4 distribution. Reduced dosage of Msx2 in the Twist1 mutant background restores the expression of ephrin-A4, rescues the suture boundary and inhibits craniosynostosis. Underlining the importance of ephrin-A4, we identified heterozygous mutations in the human orthologue, EFNA4, in three of 81 patients with non-syndromic coronal synostosis. This provides genetic evidence that Twist1, Msx2 and Efna4 function together in boundary formation and the pathogenesis of coronal synostosis.
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The greater genetic load in coronal synostosis probably reflects the coronal suture's distinct embryological origin, where neural crest-derived frontal bone meets cephalic mesoderm-derived parietal bone.
“The higher genetic load associated with coronal synostosis is likely to reflect the distinct embryological origin of the coronal suture, at the boundary between the developing frontal bone (neural crest origin) and parietal bone (cephalic mesoderm).8,40”
From Craniosynostosis (2011) · cites this paper as [8]
The Introduction (page unavailable) places the coronal suture at the boundary between neural crest-derived frontal bone and mesoderm-derived parietal bone. The paper also links defects at this boundary to coronal synostosis, but it does not establish that coronal synostosis has a higher genetic load than other forms or that this difference reflects the boundary’s embryological origin. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTwist1 has a key role in maintaining the boundary between neural crest and cephalic mesoderm at the developing coronal suture.
“Twist1 has a key role in maintaining the boundary between neural crest and cephalic mesoderm at the site of the developing coronal suture.8”
From Craniosynostosis (2011) · cites this paper as [8]
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- Authors
- Merrill, A. E., Bochukova, E. G., Brugger, S. M., Ishii, M., Pilz, D. T., Wall, S. A., Lyons, K. M., Wilkie, A. O. M., & Maxson, R. E.
- Affiliations
- University of Southern California (US)
- John Radcliffe Hospital (GB)
- University of California, Los Angeles (US)
- University Hospital of Wales (GB)
- Corresponding author
- Merrill, Amy E.
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-03-15
- Volume
- 15
- Issue
- 8
- Pages
- 1319-1328
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2128550660
- Cited by
- 206
- References
- 52
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 10 · 2023: 3 · 2022: 7 · 2021: 11 · 2020: 11 · 2019: 11 · 2018: 8 · 2017: 14 · 2016: 15 · 2015: 9 · 2014: 11 · 2013: 18 · 2012: 15
- FWCI
- 6.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- Human Molecular Genetics (publishedVersion, other-oa)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- American Heart Association
- Wellcome Trust
- National Institutes of Health (DE12941)
- National Heart, Lung, and Blood Institute (T32HL007895)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR-44528, R01AR044528)
- National Institute of Dental and Craniofacial Research (DE 12941, R01DE016320, R01DE012450, DE12450, P01DE012941)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Craniofacial Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › dental development and anomalies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Cleft Lip and Palate Research
- Keywords
- craniosynostosis, coronal synostosis, Eph/ephrin signaling, TWIST1, Msx2, cell mixing, coronal suture, nonsyndromic craniosynostosis, haploinsufficiency
- MeSH terms
- Animals, Base Sequence, Cells, Cultured, Chlorocebus aethiops, Cranial Sutures, Craniosynostoses, DNA-Binding Proteins, Embryo, Mammalian, Heterozygote, Humans, Immunohistochemistry, Mesoderm, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, Mutation, Neural Crest, Nuclear Proteins, Phenotype, Tumor Cells, Cultured, Signal Transduction, Homeodomain Proteins, Gene Expression Regulation, Developmental, COS Cells, Receptors, Eph Family, Ephrins, Ephrin-A2, Ephrin-A4, Mice, Twist-Related Protein 1
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