Identification of sonic hedgehog-regulated genes and biological processes in the cranial neural crest mesenchyme by comparative transcriptomics
Abstract Background 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 deve...
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| Format: | Article |
| Language: | English |
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BMC
2018-06-01
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| Series: | BMC Genomics |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12864-018-4885-5 |
| _version_ | 1819136355076145152 |
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| author | Joshua L. Everson Dustin M. Fink Hannah M. Chung Miranda R. Sun Robert J. Lipinski |
| author_facet | Joshua L. Everson Dustin M. Fink Hannah M. Chung Miranda R. Sun Robert J. Lipinski |
| author_sort | Joshua L. Everson |
| collection | DOAJ |
| description | Abstract Background 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. 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. Results Using 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. Conclusions We 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. |
| first_indexed | 2024-12-22T10:33:39Z |
| format | Article |
| id | doaj.art-115bfc797eab4171b305fc43de2ce4a5 |
| institution | Directory Open Access Journal |
| issn | 1471-2164 |
| language | English |
| last_indexed | 2024-12-22T10:33:39Z |
| publishDate | 2018-06-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Genomics |
| spelling | doaj.art-115bfc797eab4171b305fc43de2ce4a52022-12-21T18:29:15ZengBMCBMC Genomics1471-21642018-06-0119111110.1186/s12864-018-4885-5Identification of sonic hedgehog-regulated genes and biological processes in the cranial neural crest mesenchyme by comparative transcriptomicsJoshua L. Everson0Dustin M. Fink1Hannah M. Chung2Miranda R. Sun3Robert J. Lipinski4Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-MadisonDepartment of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-MadisonDepartment of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-MadisonDepartment of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-MadisonDepartment of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-MadisonAbstract Background 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. 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. Results Using 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. Conclusions We 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.http://link.springer.com/article/10.1186/s12864-018-4885-5Sonic hedgehogHedgehog target geneCranial neural crest cellFrontonasal prominenceMedial nasal processOrofacial development |
| spellingShingle | Joshua L. Everson Dustin M. Fink Hannah M. Chung Miranda R. Sun Robert J. Lipinski Identification of sonic hedgehog-regulated genes and biological processes in the cranial neural crest mesenchyme by comparative transcriptomics BMC Genomics Sonic hedgehog Hedgehog target gene Cranial neural crest cell Frontonasal prominence Medial nasal process Orofacial development |
| title | Identification of sonic hedgehog-regulated genes and biological processes in the cranial neural crest mesenchyme by comparative transcriptomics |
| title_full | Identification of sonic hedgehog-regulated genes and biological processes in the cranial neural crest mesenchyme by comparative transcriptomics |
| title_fullStr | Identification of sonic hedgehog-regulated genes and biological processes in the cranial neural crest mesenchyme by comparative transcriptomics |
| title_full_unstemmed | Identification of sonic hedgehog-regulated genes and biological processes in the cranial neural crest mesenchyme by comparative transcriptomics |
| title_short | Identification of sonic hedgehog-regulated genes and biological processes in the cranial neural crest mesenchyme by comparative transcriptomics |
| title_sort | identification of sonic hedgehog regulated genes and biological processes in the cranial neural crest mesenchyme by comparative transcriptomics |
| topic | Sonic hedgehog Hedgehog target gene Cranial neural crest cell Frontonasal prominence Medial nasal process Orofacial development |
| url | http://link.springer.com/article/10.1186/s12864-018-4885-5 |
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