Previously, we reported we report the recreation of congenital human Craniosynostosis (CS) phenotypes without extra-cranial deformities in transgenic mice with NELL-1 over-expression. CS phenotypes in NELL-1 transgenic mice ranged from compound synostoses such as craniotelencephalic dysplasia to simple synostoses. In vitro, NELL-1 over-expression promoted calvarial osteoblast differentiation and mineralization, and concomitantly altered bone differentiation marker and growth factor expression. The objective of this study is to investigate the interaction of NELL-1 with known CS candidate genes like FGF/FGFRs in premature suture closure. Methods: Analysis of the potential NELL-1 promoter region was performed. CBFA-1 was transfected into calvarial osteoblasts Administration of exogenous TFG-ß1, FGF2, IGF1 & 2, BMP2, VEGF, and PDGF to calvarial osteoblasts to examine the expression NELL-1. Results:. Promoter region showed a well-conserved CBDA-1 (runt family) binding site, OSE2 with a core sequence AACCACA. Transfection with CBFA-1 induced NELL-1 expression. Only TFG-ß1 and FGF2 increased NELL-1 expression. CONCLUSION: Mechanistically, CBFA-1, which regulates the commitment of mesenchymal cells to the osteoblast lineage, has been strongly associated with FGF2/FGFR1 models of CS development. Both FGF2 and TGF-ß1 are known to induce or modulate CBFA-1 expression, respectively. We postulate that because NELL-1 is regulated by CBFA-1, which in turn is regulated by FGFR1 and possibly TGF-ß, NELL-1 may be a common denominator in FGF- and TGF-ß-dependent pathways for premature suture closure as an osteoblast-specific, down-stream effector. Mechanistically, NELL-1 induces suture closure by promoting calvarial bone formation. Supported by NIH K23 DE00422, AAOF, and CRC/NIH RR00865.

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