ABSTRACT
BACKGROUND: Apert syndrome (AS) is characterized by craniosynostosis, midfacial hypoplasia, and bony syndactyly. It is an autosomal dominantly inherited disease caused by point mutations (S252W or P253R) in fibroblast growth factor receptor (FGFR) 2. These mutations cause activation of FGFR2 depending on ligand binding. Recently, an AS mouse model, Fgfr2(+/) (S252W) , showed phenotypes similar to those of AS patients. We previously reported that the soluble form of FGFR2(S252W) (sFGFR2IIIc(S252W) ) efficiently inhibits enhanced osteoblastic differentiation caused by FGFR2 activation in AS in vitro, presumably because FGFs binding to FGFRs is interrupted. In this study, we developed Fgfr2(+/) (S252W) (Ap) mice expressing the sFGFR2IIIc(S252W) protein, and we investigated the effects of sFGFR2IIIc(S252W) on AS-like phenotypes. RESULTS: In Ap mice, the coronal suture (CS) was fused prematurely at P1. In addition, the mice exhibited a widened interfrontal suture (IFS) with ectopic bone and thickened cartilage formation. In Fgfr2(+/) (S252W) sFGFR2IIIc(S252W) (Ap/Sol) mice, the CS was similar to that of wild-type mice. Ap/Sol mice did not show any ectopic bone or cartilage formation in the IFS, but showed a wider IFS than that of the wild-type mice. CONCLUSIONS: sFGFR2IIIc(S252W) may partially prevent craniosynostosis in the Apert mouse model by affecting the CS and IFS in vivo.
Subject(s)
Acrocephalosyndactylia , Embryo, Mammalian , Embryonic Development , Mutation, Missense , Receptor, Fibroblast Growth Factor, Type 2 , Acrocephalosyndactylia/embryology , Acrocephalosyndactylia/genetics , Acrocephalosyndactylia/pathology , Acrocephalosyndactylia/prevention & control , Amino Acid Substitution , Animals , Disease Models, Animal , Embryo, Mammalian/embryology , Embryo, Mammalian/pathology , Mice , Mice, Mutant Strains , Receptor, Fibroblast Growth Factor, Type 2/genetics , Receptor, Fibroblast Growth Factor, Type 2/metabolismABSTRACT
Mutations in the gene encoding the zinc finger transcription factor GLI3 (GLI-Kruppel family member 3) have been identified in patients with Grieg cephalopolysyndactyly syndrome in which premature fusion of calvarial suture (craniosynostosis) is an infrequent but important feature. Here, we show that Gli3 acts as a repressor in the developing murine calvaria and that Dlx5, Runx2 type II isoform (Runx2-II), and Bmp2 are expressed ectopically in the calvarial mesenchyme, which results in aberrant osteoblastic differentiation in Gli3-deficient mouse (Gli3(Xt-J/Xt-J)) and resulted in craniosynostosis. At the same time, enhanced activation of phospho-Smad1/5/8 (pSmad1/5/8), which is a downstream mediator of canonical Bmp signaling, was observed in Gli3(Xt-J/Xt-J) embryonic calvaria. Therefore, we generated Gli3;Runx2 compound mutant mice to study the effects of decreasing Runx2 dosage in a Gli3(Xt-J/Xt-J) background. Gli3(Xt-J/Xt-J) Runx2(+/-) mice have neither craniosynostosis nor additional ossification centers in interfrontal suture and displayed a normalization of Dlx5, Runx2-II, and pSmad1/5/8 expression as well as sutural mesenchymal cell proliferation. These findings suggest a novel role for Gli3 in regulating calvarial suture development by controlling canonical Bmp-Smad signaling, which integrates a Dlx5/Runx2-II cascade. We propose that targeting Runx2 might provide an attractive way of preventing craniosynostosis in patients.
Subject(s)
Acrocephalosyndactylia/embryology , Core Binding Factor Alpha 1 Subunit/metabolism , Kruppel-Like Transcription Factors/metabolism , Nerve Tissue Proteins/metabolism , Signal Transduction , Skull/embryology , Acrocephalosyndactylia/genetics , Acrocephalosyndactylia/prevention & control , Animals , Cell Differentiation , Core Binding Factor Alpha 1 Subunit/genetics , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , Kruppel-Like Transcription Factors/genetics , Matrix Metalloproteinases, Secreted/genetics , Matrix Metalloproteinases, Secreted/metabolism , Mesoderm/embryology , Mice , Mice, Mutant Strains , Nerve Tissue Proteins/genetics , Osteoblasts/metabolism , Smad Proteins , Zinc Finger Protein Gli3ABSTRACT
Acrocephalosyndactyly type I or Apert syndrome is characterized by craniosynostosis, particular dysmorphic features and abnormalities of the hands and feet. Rarely, polydactyly of the toes has been reported, and in this event the diagnosis of Carpenter syndrome must be discussed. A case of atypical Acrocephalosyndactyly type I syndrome with partial preaxial polydactyly is reported. Despite this preaxial polydactyly a diagnosis of Apert syndrome consecutive to a new mutation was made, and the possibility of recurrence considered to be highly improbable.
