Expression of Indian Hedgehog, BMP-4 and Noggin in Craniosynostosis Induced by Fetal Constraint

Abstract

Indian Hedgehog (Ihh), bone morphogenetic protein (BMP), and its antagonist Noggin play an important regulatory role in bone formation. We used an animal model to study the role of these molecules in craniosynostosis induced by fetal constraint. C57Bl/6 mice underwent cervical cerclage on the 18th day of gestation, and their pups were harvested 48 and 72 hours beyond the normal gestational period. Constrained and control calvariae were examined for expression of BMP-4, Noggin, Histone H4C, Ihh, Sonic Hedgehog (Shh), and Patched 1 (Ptch1), one of the Hh transcriptional target molecules/Hh receptors. Constraint-induced suture fusion was associated with decreased expression of Ihh and Noggin, whereas BMP-4 was expressed in both control and constrained sutures. Ptch1 colocalized with Ihh-positive osteogenic cells at the osteogenic fronts, but not with Shh transcripts, suggesting that Ihh, but not Shh, regulates Ptch1 expression in cranial suture development. Histone H4C was preferentially expressed in Ihh-positive cells, indicating that Ihh may regulate osteogenic cell proliferation at the osteogenic fronts. These results suggest a role for Ihh and Noggin signaling in constraint-induced craniosynostosis.