title: Left-sided embryonic expression of the BCL-6 corepressor, BCOR, is required for vertebrate laterality determination.
abstract: Oculofaciocardiodental (OFCD) syndrome is an X-linked male lethal condition encompassing cardiac septal defects, as well as ocular and dental anomalies. The gene mutated in OFCD syndrome, the BCL-6 corepressor (BCOR), is part of a transcriptional repression complex whose transcriptional targets remain largely unknown. We reviewed cases of OFCD syndrome and identified patients exhibiting defective lateralization including dextrocardia, asplenia and intestinal malrotation, suggesting that BCOR is required in normal laterality determination. To study the function of BCOR, we used morpholino oligonucleotides (MOs) to knockdown expression of xtBcor in Xenopus tropicalis, thus creating an animal model for OFCD syndrome. The resulting tadpoles had cardiac and ocular features characteristic of OFCD syndrome. Reversed cardiac orientation and disorganized gut patterning were seen when MOs were injected into the left side of embryos, demonstrating a left-sided requirement for xtBcor in lateral determination in Xenopus. Ocular defects displayed no left-right bias and included anterior and posterior segment disorders such as microphthalmia and coloboma. Expression of xtPitx2c was shown to be downregulated when xtBcor was depleted. This identifies a pathway in which xtBcor is required for lateral specification, a process intrinsically linked to correct cardiac septal development.
authors.affiliation: Academic Unit of Medical Genetics and Regional Genetic Service, St Mary's Hospital, Manchester, UK.
authors.forename: Emma N
authors.initials: EN
authors.lastname: Hilton
authors.forename: Forbes D C
authors.initials: FD
authors.lastname: Manson
authors.forename: Jill E
authors.initials: JE
authors.lastname: Urquhart
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Johnston
authors.forename: Anne M
authors.initials: AM
authors.lastname: Slavotinek
authors.forename: Peter
authors.initials: P
authors.lastname: Hedera
authors.forename: Eva-Lena
authors.initials: EL
authors.lastname: Stattin
authors.forename: Ann
authors.initials: A
authors.lastname: Nordgren
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Black
mesh_terms: D000818:Animals; D019521:Body Patterning; D041321:Chromosomes, Human, X; D019465:Craniofacial Abnormalities / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D005128:Eye Diseases / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology; D006801:Humans; D008297:Male; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics*; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics*; D013577:Syndrome; D014018:Tissue Distribution; D014981:Xenopus / Q000378:metabolism
chemical_list: C084103:BCL6 protein, human; C411984:BCOR protein, human; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins