Differential Expression of Extracellular Matrix-Mediated Pathways in Single-Suture Craniosynostosis

Abstract

Craniosynostosis is a disease defined by premature fusion of one or more cranial sutures. The mechanistic pathology of single-suture craniosynostosis is complex and while a number of genetic biomarkers and environmental predispositions have been identified, in many cases the causes remain controversial and inconclusive. In this study, gene expression data from 199 patients with isolated sagittal (n = 100), unilateral coronal (n = 50), and metopic (n = 49) synostosis are compared against both a control population (n = 50), as well as each other. After controlling for variables contributing to potential bias, FGF7, SFRP4, and VCAM1 emerged as genes associated with single-suture craniosynostosis due to their significantly large changes in gene expression compared to the control population. Pathway analysis implicated focal adhesion and extracellular matrix (ECM)-receptor interaction as differentially regulated gene networks when comparing all cases of single-suture synostosis and controls. Lastly, overall gene expression was found to be highly conserved between coronal and metopic cases, as evidenced by the fact that WNT2 and IGFBP2 were the only genes differentially regulated to a significantly large extent in a direct comparison. The identification of genes and gene networks associated with Fgf/Igf/Wnt signaling and ECM-mediated focal adhesion not only support the involvement of biomarkers previously reported to be related to craniosynostosis, but also introduce novel transcripts and pathways that may play critical roles in its pathogenesis.

Activation of the IGF1 pathway mediates changes in cellular contractility and motility in single-suture craniosynostosis

“…Recently, transcriptomic analysis has identified differential gene expression in both SSC osteoblasts and controls (Stamper et al, 2011). Furthermore, these differences in the correlation structure of the transcriptome have shown upregulation of IGF1 activity in calvarial SSC osteoblasts (Stamper et al, 2011). In this study, SSC osteoblasts with elevated IGF1 expression were observed to have higher traction forces than controls.…”

“…This suggests that IGF1 influences migration and contributes to the development of SSC. In our previous study (Stamper et al, 2011), we demonstrated that differential IGF1 signaling results in upregulation of ECMmediated focal adhesions. Moreover, IGF1 signaling has also been implicated in mediating focal adhesion formation and cell migration (Manes et al, 1999;Andersson et al, 2009).…”

“…Mutations and/or overexpression in IGF1 and IGF1R has been associated with SSC and also results in growth retardation in both humans and mice Liu et al, 1993;Woods et al, 1996;Cunningham et al, 2011). Recently, transcriptomic analysis has identified differential gene expression in both SSC osteoblasts and controls (Stamper et al, 2011). Furthermore, these differences in the correlation structure of the transcriptome have shown upregulation of IGF1 activity in calvarial SSC osteoblasts (Stamper et al, 2011).…”

“…As previously described (Stamper et al, 2011;Park et al, 2015), 84% of the eligible cases approached for consent were enrolled in the study. Computed tomography (CT) scans identified and confirmed isolated sagittal, coronal, metopic or lambdoid synostosis.…”

“…As previously described (Stamper et al, 2011;Park et al, 2015), harvested calvaria samples were obtained from individuals undergoing surgery for sagittal, coronal, metopic or lambdoid synostosis (Fig. S1C,D and Table S1).…”