Human Molecular Genetics Advance Access originally published online on May 21, 2007
Human Molecular Genetics 2007 16(14):1773-1782; doi:10.1093/hmg/ddm125
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Left-sided embryonic expression of the BCL-6 corepressor, BCOR, is required for vertebrate laterality determination
1 Academic Unit of Medical Genetics and Regional Genetic Service, St Mary's Hospital, Manchester, UK, 2 Centre for Molecular Medicine, The University of Manchester, Manchester, UK, 3 Manchester Royal Eye Hospital, Central Manchester and Manchester Children's University Hospitals NHS Trust, Oxford Road, Manchester, UK, 4 Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA, 5 Department of Pediatrics, Division of Genetics, University of California, San Francisco, CA, USA, 6 Department of Neurology, Vanderbilt University, Nashville, TN, USA, 7 Department of Clinical Genetics, Umeå University Hospital, Umeå, Sweden and 8 Department of Molecular Medicine, Clinical Genetics Unit, Karolinska Institutet, Stockholm, Sweden
* To whom correspondence should be addressed at: Department of Clinical Genetics, Central Manchester and Manchester Children's University Hospitals NHS Trust, St Mary's Hospital, Hathersage Road, Manchester M13 0JH, UK. Tel: +1 612766269; Fax: +1 612766145; Email: gblack{at}man.ac.uk
Received February 28, 2007; Accepted May 3, 2007
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.