Foxc1 controls the growth of the murine frontal bone rudiment by direct regulation of a Bmp response threshold of Msx2
ABSTRACT 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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ABSTRACT: Congenital bony syngnathia, a rare but severe human birth defect, is characterized by bony fusion of the mandible to the maxilla. However, the genetic mechanisms underlying this birth defect are poorly understood, largely due to limitation of available animal models. Here we present evidence that transgenic expression of Bmp4 in neural crest cells causes a series of craniofacial malformations in mice, including a bony fusion between the maxilla and hypoplastic mandible, resembling the bony syngnathia syndrome in humans. In addition, the anterior portion of the palatal shelves emerged from the mandibular arch instead of the maxilla in the mutants. Gene expression assays showed an altered expression of several facial patterning genes, including Hand2, Dlx2, Msx1, Barx1, Foxc2 and Fgf8, in the maxillary and mandibular processes of the mutants, indicating mis-patterned cranial neural crest (CNC) derived cells in the facial region. However, despite of formation of cleft palate and ectopic cartilage, forced expression of a constitutively active form of BMP receptor-Ia (caBmprIa) in CNC lineage did not produce the syngnathia phenotype, suggesting a non-cell autonomous effect of the augmented BMP4 signaling. Our studies demonstrate that aberrant BMP4-mediated signaling in CNC cells leads to mis-patterned facial skeleton and congenital bony syngnathia, and suggest an implication of mutations in BMP signaling pathway in human bony syngnathia.Developmental Biology 04/2014; 391(2). DOI:10.1016/j.ydbio.2014.04.013 · 3.64 Impact Factor
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ABSTRACT: The aim of this study was to detect FOXC1 expression in gastric tissues and the clinical significance of FOXC1 in the development, progression and metastasis of GC patients. We screened the expression of FOXC1 in GC by Affymetrix U133 plus 2.0 Gene Chip Array and we found FOXC1 expression was significantly higher in GC tissues than in controls by microarray. Furthermore, we validated the expression levels of FOXC1 by real-time quantitative RT-PCR (qRT-PCR) and immunohistochemistry (IHC). Our study showed that the expression levels of FOXC1 mRNA and protein in GC tissues were significantly higher than those in corresponding non-tumor tissues. High expression of FOXC1 correlated with the degree of histological differentiation (P<0.01), TNM stage (P<0.001), invasive depth (P<0.05), lymph node metastasis (P<0.05) and distant metastasis (P<0.01). Survival analysis revealed that patients with high expression levels of FOXC1 showed lower overall survival rate than those with low expression levels (P<0.001). Multivariate analysis showed that high FOXC1 protein expression was an independent prognostic factor for GC patients (P<0.01). Up-expression of FOXC1 may play a key role in progression of GC, and FOXC1 expression may serve as a useful marker for predicting the outcome of patients with GC. This article is protected by copyright. All rights reserved.Histopathology 12/2013; 64(7). DOI:10.1111/his.12347 · 3.30 Impact Factor
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ABSTRACT: The frontal and parietal bones form the major part of the calvarium and their primordia appear at the basolateral region of the head and grow apically. A spontaneous loss of Foxc1 function mutant mouse, congenital hydrocephalus (Foxc1(ch/ch) ), results in congenital hydrocephalus accompanied by defects in the apical part of the skull vault. We found that during the initiation stage of apical growth of the frontal bone primordium in the Foxc1(ch/ch) mouse, the Runx2 expression domain extended only to the basal side and bone sialoprotein (Bsp) and N-cadherin expression domains appeared only in the basal region. Fluorescent dye (DiI) labeling of the frontal primordium by ex-utero surgery confirmed that apical extension of the frontal bone primordium of the mouse was severely retarded, while extension to the basal side underneath the brain was largely unaffected. Consistent with this observation, decreased cell proliferation activity was seen at the apical tip but not the basal tip of the frontal bone primordium as determined by double detection of Runx2 transcripts and BrdU incorporation. Furthermore, expression of the osteogenic-related genes Bmp4 and -7 was observed only in the basal part of the meninges during the initiation period of primordium growth. These results suggest that a loss of Foxc1 function affects skull bone formation of the apical region and that Bmp expression in the meninges might influence the growth of the calvarial bone primordium.Congenital Anomalies 01/2014; 54(3). DOI:10.1111/cga.12053 · 0.78 Impact Factor