Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Base Sequence
-
COS Cells
-
Cells, Cultured
-
Chlorocebus aethiops
-
Cranial Sutures / metabolism*
-
Craniosynostoses / metabolism*
-
Craniosynostoses / pathology*
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / metabolism
-
Embryo, Mammalian
-
Ephrin-A2 / genetics
-
Ephrin-A2 / metabolism
-
Ephrin-A4 / genetics
-
Ephrin-A4 / metabolism
-
Ephrins / metabolism*
-
Gene Expression Regulation, Developmental
-
Heterozygote
-
Homeodomain Proteins / genetics
-
Homeodomain Proteins / metabolism
-
Humans
-
Immunohistochemistry
-
Mesoderm / cytology
-
Mesoderm / metabolism*
-
Mice
-
Mice, Inbred C57BL
-
Mice, Transgenic
-
Molecular Sequence Data
-
Mutation
-
Neural Crest / cytology
-
Neural Crest / metabolism*
-
Nuclear Proteins / genetics
-
Nuclear Proteins / metabolism
-
Phenotype
-
Receptors, Eph Family / metabolism*
-
Signal Transduction
-
Tumor Cells, Cultured
-
Twist-Related Protein 1 / genetics
-
Twist-Related Protein 1 / metabolism
Substances
-
DNA-Binding Proteins
-
Ephrin-A2
-
Ephrin-A4
-
Ephrins
-
Homeodomain Proteins
-
MSX2 protein
-
Nuclear Proteins
-
Twist-Related Protein 1
-
Twist1 protein, mouse
-
Receptors, Eph Family
Associated data
-
GENBANK/AC010899
-
GENBANK/AC079834
-
GENBANK/AJ006353
-
RefSeq/NM_001405
-
RefSeq/NM_004438
-
RefSeq/NM_005227
-
RefSeq/NT_004487
-
RefSeq/NT_011255