{"data":{"id":"10.25384/sage.c.4161977.v1","type":"dois","attributes":{"doi":"10.25384/sage.c.4161977.v1","prefix":"10.25384","suffix":"sage.c.4161977.v1","identifiers":[],"alternateIdentifiers":[],"creators":[{"name":"N.L. Hammond","affiliation":[],"nameIdentifiers":[]},{"name":"K.J. Brookes","affiliation":[],"nameIdentifiers":[]},{"name":"M.J. Dixon","affiliation":[],"nameIdentifiers":[]}],"titles":[{"title":"Ectopic Hedgehog Signaling Causes Cleft Palate and Defective Osteogenesis"}],"publisher":"Figshare","container":{},"publicationYear":2018,"subjects":[{"subject":"110599 Dentistry not elsewhere classified","subjectScheme":"FOR"},{"subject":"FOS: Clinical medicine","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"91299 Materials Engineering not elsewhere classified","subjectScheme":"FOR"},{"subject":"FOS: Materials engineering","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"}],"contributors":[],"dates":[{"date":"2018-07-11","dateType":"Created"},{"date":"2018-07-11","dateType":"Updated"},{"date":"2018","dateType":"Issued"}],"language":null,"types":{"ris":"GEN","bibtex":"misc","citeproc":"article","schemaOrg":"Collection","resourceType":"Collection","resourceTypeGeneral":"Collection"},"relatedIdentifiers":[{"relationType":"IsSupplementTo","relatedIdentifier":"10.1177/0022034518785336","relatedIdentifierType":"DOI"},{"relationType":"IsIdenticalTo","relatedIdentifier":"10.25384/sage.c.4161977","relatedIdentifierType":"DOI"}],"relatedItems":[],"sizes":[],"formats":[],"version":null,"rightsList":[{"rights":"CC BY 4.0","rightsUri":"https://creativecommons.org/licenses/by/4.0"}],"descriptions":[{"description":"Cleft palate is a common birth defect that frequently occurs in human congenital malformations caused by mutations in components of the Sonic Hedgehog (S\u003ci\u003eHH\u003c/i\u003e) signaling cascade. \u003ci\u003eShh\u003c/i\u003e is expressed in dynamic, spatiotemporal domains within epithelial rugae and plays a key role in driving epithelial-mesenchymal interactions that are central to development of the secondary palate. However, the gene regulatory networks downstream of Hedgehog (Hh) signaling are incompletely characterized. Here, we show that ectopic Hh signaling in the palatal mesenchyme disrupts oral-nasal patterning of the neural crest cell–derived ectomesenchyme of the palatal shelves, leading to defective palatine bone formation and fully penetrant cleft palate. We show that a series of Fox transcription factors, including the novel direct target \u003ci\u003eFoxl1\u003c/i\u003e, function downstream of Hh signaling in the secondary palate. Furthermore, we demonstrate that Wnt/bone morphogenetic protein (BMP) antagonists, in particular \u003ci\u003eSostdc1\u003c/i\u003e, are positively regulated by Hh signaling, concomitant with downregulation of key regulators of osteogenesis and BMP signaling effectors. Our data demonstrate that ectopic Hh-Smo signaling downregulates Wnt/BMP pathways, at least in part by upregulating \u003ci\u003eSostdc1\u003c/i\u003e, resulting in cleft palate and defective osteogenesis.","descriptionType":"Abstract"}],"geoLocations":[],"fundingReferences":[],"xml":"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","url":"https://figshare.com/collections/Ectopic_Hedgehog_Signaling_Causes_Cleft_Palate_and_Defective_Osteogenesis/4161977/1","contentUrl":null,"metadataVersion":1,"schemaVersion":"http://datacite.org/schema/kernel-3","source":"api","isActive":true,"state":"findable","reason":null,"viewCount":0,"viewsOverTime":[],"downloadCount":0,"downloadsOverTime":[],"referenceCount":1,"citationCount":0,"citationsOverTime":[],"partCount":0,"partOfCount":0,"versionCount":0,"versionOfCount":0,"created":"2018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