Left-sided embryonic expression of the BCL-6 corepressor, BCOR, is required for vertebrate laterality determination
Left-sided embryonic expression of the BCL-6 corepressor, BCOR, is required for vertebrate laterality determination
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DOI：
10.1093/hmg/ddm125
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发表时间：
2007-07-15
影响因子：
3.5
通讯作者：
Black, Graeme C. M.
中科院分区：
文献类型：
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作者：
Hilton, Emma N.;Manson, Forbes D. C.;Black, Graeme C. M.
眼面心齿综合征（OFCD）是一种X染色体连锁的男性致死性疾病，包括心脏间隔缺损，以及眼部和牙齿异常。在OFCD综合征中突变的基因BCL-6辅阻遏物（BCOR）是转录抑制复合物的一部分，其转录靶点在很大程度上仍然未知。我们回顾了OFCD综合征的病例，并确定了表现出偏侧性缺陷的患者，包括右位心、无脾和肠旋转不良，这表明在正常偏侧性确定中需要BCOR。为了研究BCOR的功能，我们使用吗啉代寡核苷酸（MOs）敲低热带爪蟾xtBcor的表达，从而建立了OFCD综合征的动物模型。由此产生的蝌蚪具有OFCD综合征的心脏和眼部特征。反转的心脏方向和紊乱的肠道图案时，看到MO注入左侧的胚胎，表明左侧的xtBcor在非洲爪蟾的横向测定的要求。眼缺损显示无左右偏倚，包括前节和后节疾病，如小眼球和缺损。当xtBcor被耗尽时，xtPitx 2c的表达被显示为下调。这确定了一个途径，其中xtBcor是需要横向规格，一个过程内在地联系到正确的心脏间隔的发展。
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.