Abstract
BackgroundThe evolutionarily conserved Sonic Hedgehog (Shh) signaling pathway is essential for embryogenesis and orofacial development. SHH ligand secreted from the surface ectoderm activates pathway activity in the underlying cranial neural crest cell (cNCC)-derived mesenchyme of the developing upper lip and palate. Disruption of Shh signaling causes orofacial clefts, but the biological action of Shh signaling and the full set of Shh target genes that mediate normal and abnormal orofacial morphogenesis have not been described.ResultsUsing comparative transcriptional profiling, we have defined the Shh-regulated genes of the cNCC-derived mesenchyme. Enrichment analysis demonstrated that in cultured cNCCs, Shh-regulated genes are involved in smooth muscle and chondrocyte differentiation, as well as regulation of the Forkhead family of transcription factors, G1/S cell cycle transition, and angiogenesis. Next, this gene set from Shh-activated cNCCs in vitro was compared to the set of genes dysregulated in the facial primordia in vivo during the initial pathogenesis of Shh pathway inhibitor-induced orofacial clefting. Functional gene annotation enrichment analysis of the 112 Shh-regulated genes with concordant expression changes linked Shh signaling to interdependent and unique biological processes including mesenchyme development, cell adhesion, cell proliferation, cell migration, angiogenesis, perivascular cell markers, and orofacial clefting.ConclusionsWe defined the Shh-regulated transcriptome of the cNCC-derived mesenchyme by comparing the expression signatures of Shh-activated cNCCs in vitro to primordial midfacial tissues exposed to the Shh pathway inhibitor in vivo. In addition to improving our understanding of cNCC biology by determining the identity and possible roles of cNCC-specific Shh target genes, this study presents novel candidate genes whose examination in the context of human orofacial clefting etiology is warranted.
Highlights
The evolutionarily conserved Sonic Hedgehog (Shh) signaling pathway is essential for embryogenesis and orofacial development
We show that Shh regulates key angiogenic and perivascular genes in isolated cranial neural crest cell (cNCC), and that Shh regulation of angiogenic and perivascular genes is disrupted during the initial pathogenesis of cleft lip
These results suggest that Shh signaling may promote the differentiation of multipotent cNCCs to endothelium-supporting perivascular cells/pericytes during craniofacial morphogenesis, and disruption of this molecular-cellular program may contribute to Orofacial clefts (OFCs) pathogenesis
Summary
The evolutionarily conserved Sonic Hedgehog (Shh) signaling pathway is essential for embryogenesis and orofacial development. SHH ligand secreted from the surface ectoderm activates pathway activity in the underlying cranial neural crest cell (cNCC)-derived mesenchyme of the developing upper lip and palate. Orofacial clefts (OFCs) are the most common human craniofacial birth defects, occurring in 1–2 per 1000 live births [1]. While the overall frequency of the most prevalent form of OFCs in humans, cleft lip with or without cleft palate, is approximately 0.1% in the general population, concurrence rates in monozygotic twins, dizygotic twins, and siblings are 35–50, 5%, and 3–5%, respectively [4, 7]. At gestational day (GD)9.25 in the mouse, the frontonasal prominence
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