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Authordc.contributor.authorSignore Ahumada, Iskra 
Authordc.contributor.authorJerez, Carolina 
Authordc.contributor.authorFigueroa, Diego 
Authordc.contributor.authorSuazo Sanhueza, José Lorenzo 
Authordc.contributor.authorMarcelain Cubillos, Katherine 
Authordc.contributor.authorCerda Arancibia, Óscar 
Authordc.contributor.authorColombo Flores, Alicia 
Admission datedc.date.accessioned2017-11-28T16:03:15Z
Available datedc.date.available2017-11-28T16:03:15Z
Publication datedc.date.issued2016
Cita de ítemdc.identifier.citationBirth Defects Research (Part A) 106:814–830 (2016) 815es_ES
Identifierdc.identifier.issn1542-0752
Identifierdc.identifier.other10.1002/bdra.23546
Identifierdc.identifier.urihttps://repositorio.uchile.cl/handle/2250/145875
Abstractdc.description.abstractBackground: Orofacial clefts (OFCs) are common birth defects, which include a range of disorders with a complex etiology affecting formation of craniofacial structures. Some forms of syndromic OFCs are produced by defects in the cholesterol pathway. The principal enzyme of the cholesterol pathway is the 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR). Our aim is to study whether defects of HMGCR function would produce orofacial malformation similar to those found in disorders of cholesterol synthesis. Methods: We used zebrafish hmgcrb mutants and HMGCR inhibition assay using atorvastatin during early and late stages of orofacial morphogenesis in zebrafish. To describe craniofacial phenotypes, we stained cartilage and bone and performed in situ hybridization using known craniofacial markers. Also, we visualized neural crest cell migration in a transgenic fish. Results: Our results showed that mutants displayed loss of cartilage and diminished orofacial outgrowth, and in some cases palatal cleft. Late treatments with statin show a similar phenotype. Affected-siblings displayed a moderate phenotype, whereas early-treated embryos had a minor cleft. We found reduced expression of the downstream component of Sonic Hedgehog-signaling gli1 in ventral brain, oral ectoderm, and pharyngeal endoderm in mutants and in late atorvastatin-treated embryos. Conclusion: Our results suggest that HMGCR loss-of-function primarily affects postmigratory cranial neural crest cells through abnormal Sonic Hedgehog signaling, probably induced by reduction in metabolites of the cholesterol pathway. Malformation severity correlates with the grade of HMGCR inhibition, developmental stage of its disruption, and probably with availability of maternal lipids. Together, our results might help to understand the spectrum of orofacial phenotypes found in cholesterol synthesis disorderses_ES
Lenguagedc.language.isoenes_ES
Publisherdc.publisherWileyes_ES
Type of licensedc.rightsAttribution-NonCommercial-NoDerivs 3.0 Chile*
Link to Licensedc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/cl/*
Sourcedc.sourceBirth Defects Research (Part A)es_ES
Keywordsdc.subjectHMGCRes_ES
Keywordsdc.subjectOrofacial malformationes_ES
Keywordsdc.subjectOrofacial cleftes_ES
Keywordsdc.subjectCholesterol pathwayes_ES
Keywordsdc.subjectSHh-signalinges_ES
Keywordsdc.subjectStatinses_ES
Keywordsdc.subjectZebrafishes_ES
Títulodc.titleInhibition of the 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Induces Orofacial Defects in Zebrafishes_ES
Document typedc.typeArtículo de revista
Catalogueruchile.catalogadorapces_ES
Indexationuchile.indexArtículo de publicación ISIes_ES


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Attribution-NonCommercial-NoDerivs 3.0 Chile
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivs 3.0 Chile