Perturbed development of cranial neural crest cells in association with reduced sonic hedgehog signaling underlies the pathogenesis of retinoic-acid-induced cleft palate

Wang, Qi; Kurosaka, Hiroshi; Kikuchi, Masataka; Nakaya, Akihiro; Trainor, Paul A.; Yamashiro, Takashi

doi:https://doi.org/10.1242/dmm.040279

Perturbed development of cranial neural crest cells in association with reduced sonic hedgehog signaling underlies the pathogenesis of retinoic-acid-induced cleft palate

Wang, Qi; Kurosaka, Hiroshi; Kikuchi, Masataka et al.

DMM Disease Models and Mechanisms, 2019, 12(10)

アクセス数:50件（2026-02-16 23:05 集計）

固定URL: https://hdl.handle.net/11094/103553

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タイトル	Perturbed development of cranial neural crest cells in association with reduced sonic hedgehog signaling underlies the pathogenesis of retinoic-acid-induced cleft palate
著者	著者名 Wang, Qi
	NRID 1000020509369 1000020509369 ORCID 0000-0002-8956-5467 0000-0002-8956-5467 researchmap permalink kurosakahiroshi kurosakahiroshi Scopus Author ID 11839162500 11839162500 著者名 Kurosaka, Hiroshi
	NRID 1000090722538 1000090722538 著者名 Kikuchi, Masataka
	NRID 1000060301149 1000060301149 著者名 Nakaya, Akihiro
	著者名 Trainor, Paul A.
	NRID 1000070294428 1000070294428 ORCID 0000-0002-4419-9643 0000-0002-4419-9643 researchmap permalink read0051793 read0051793 Scopus Author ID 55416765600 55416765600 著者名 Yamashiro, Takashi
キーワード等	Apoptosis
	Craniofacial development
	Embryogenesis
	Retinoic acid
	Shh
	Vitamin A
内容	Wang Q., Kurosaka H., Kikuchi M., et al. Perturbed development of cranial neural crest cells in association with reduced sonic hedgehog signaling underlies the pathogenesis of retinoic-acid-induced cleft palate. DMM Disease Models and Mechanisms 12 (2019); https://doi.org/10.1242/dmm.040279.
抄録	Cleft palate (CP) is one of the most common congenital craniofacial anomalies in humans and can be caused by either single or multiple genetic and environmental factor(s). With respect to environmental factors, excessive intake of vitamin A during early pregnancy is associated with increased incidence of CP in offspring both in humans and in animal models. Vitamin A is metabolized to retinoic acid (RA); however, the pathogenetic mechanism of CP caused by altered RA signaling during early embryogenesis is not fully understood. To investigate the detailed cellular and molecular mechanism of RA-induced CP, we administered all-trans RA to pregnant mice at embryonic day (E)8.5. In the RA-treated group, we observed altered expression of Sox10, which marks cranial neural crest cells (CNCCs). Disruption of Sox10 expression was also observed at E10.5 in the maxillary component of the first branchial arch, which gives rise to secondary palatal shelves. Moreover, we found significant elevation of CNCC apoptosis in RA-treated embryos. RNA-sequencing comparisons of RA-treated embryos compared to controls revealed alterations in Sonic hedgehog (Shh) signaling. More specifically, the expression of Shh and its downstream genes Ptch1 and Gli1 was spatiotemporally downregulated in the developing face of RA-treated embryos. Consistent with these findings, the incidence of CP in association with excessive RA signaling was reduced by administration of the Shh signaling agonist SAG (Smoothened agonist). Altogether, our results uncovered a novel mechanistic association between RA-induced CP with decreased Shh signaling and elevated CNCC apoptosis.
出版者	Company of Biologists Ltd
収録物名	DMM Disease Models and Mechanisms
巻(号)	12(10)
刊行年月	2019-10-04
言語	英語
ハンドルURL	https://hdl.handle.net/11094/103553
PISSN	17548403
eISSN	17548411
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1242/dmm.040279
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCMI資源タイプ	text
DCTERMS.bibliographicCitation	DMM Disease Models and Mechanisms. 2019, 12(10)
DC.title	Perturbed development of cranial neural crest cells in association with reduced sonic hedgehog signaling underlies the pathogenesis of retinoic-acid-induced cleft palate
DC.creator	Wang, Qi
	Kurosaka, Hiroshi
	Kikuchi, Masataka
	Nakaya, Akihiro
	Trainor, Paul A.
	Yamashiro, Takashi
DC.publisher	Company of Biologists Ltd
DC.language' scheme='DCTERMS.RFC1766	英語
DC.type' scheme='DCTERMS.DCMIType	text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2019-10-04
DC.identifier	https://doi.org/10.1242/dmm.040279
DC.subject	Apoptosis
	Craniofacial development
	Embryogenesis
	Retinoic acid
	Shh
	Vitamin A
DC.description	Wang Q., Kurosaka H., Kikuchi M., et al. Perturbed development of cranial neural crest cells in association with reduced sonic hedgehog signaling underlies the pathogenesis of retinoic-acid-induced cleft palate. DMM Disease Models and Mechanisms 12 (2019); https://doi.org/10.1242/dmm.040279.
DCTERMS.abstract	Cleft palate (CP) is one of the most common congenital craniofacial anomalies in humans and can be caused by either single or multiple genetic and environmental factor(s). With respect to environmental factors, excessive intake of vitamin A during early pregnancy is associated with increased incidence of CP in offspring both in humans and in animal models. Vitamin A is metabolized to retinoic acid (RA); however, the pathogenetic mechanism of CP caused by altered RA signaling during early embryogenesis is not fully understood. To investigate the detailed cellular and molecular mechanism of RA-induced CP, we administered all-trans RA to pregnant mice at embryonic day (E)8.5. In the RA-treated group, we observed altered expression of Sox10, which marks cranial neural crest cells (CNCCs). Disruption of Sox10 expression was also observed at E10.5 in the maxillary component of the first branchial arch, which gives rise to secondary palatal shelves. Moreover, we found significant elevation of CNCC apoptosis in RA-treated embryos. RNA-sequencing comparisons of RA-treated embryos compared to controls revealed alterations in Sonic hedgehog (Shh) signaling. More specifically, the expression of Shh and its downstream genes Ptch1 and Gli1 was spatiotemporally downregulated in the developing face of RA-treated embryos. Consistent with these findings, the incidence of CP in association with excessive RA signaling was reduced by administration of the Shh signaling agonist SAG (Smoothened agonist). Altogether, our results uncovered a novel mechanistic association between RA-induced CP with decreased Shh signaling and elevated CNCC apoptosis.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	103553
citation_title	Perturbed development of cranial neural crest cells in association with reduced sonic hedgehog signaling underlies the pathogenesis of retinoic-acid-induced cleft palate
citation_author	Wang, Qi
	Kurosaka, Hiroshi
	Kikuchi, Masataka
	Nakaya, Akihiro
	Trainor, Paul A.
	Yamashiro, Takashi
citation_publisher	Company of Biologists Ltd
citation_language	英語
citation_date	2019-10-04
citation_journal_title	DMM Disease Models and Mechanisms
citation_volume	12
citation_issue	10
citation_doi	https://doi.org/10.1242/dmm.040279
citation_public_url	https://hdl.handle.net/11094/103553

Perturbed development of cranial neural crest cells in association with reduced sonic hedgehog signaling underlies the pathogenesis of retinoic-acid-induced cleft palate

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