Left-sided embryonic expression of the BCL-6 corepressor, BCOR, is required for vertebrate laterality determination.
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.
Hilton
Emma N
EN
Academic Unit of Medical Genetics and Regional Genetic Service, St Mary's Hospital, Manchester, UK.
Manson
Forbes D C
FD
Urquhart
Jill E
JE
Johnston
Jennifer J
JJ
Slavotinek
Anne M
AM
Hedera
Peter
P
Stattin
Eva-Lena
EL
Nordgren
Ann
A
Biesecker
Leslie G
LG
Black
Graeme C M
GC
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
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