Department of Cardiovascular Medicine and Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Hum Mol Genet. 2010 Sep 1;19(17):3394-401. doi: 10.1093/hmg/ddq251. Epub 2010 Jun 21.
Deficiency of the transcription factor Cited2 in mice results in cardiac malformation, adrenal agenesis, neural tube, placental defects and partially penetrant cardiopulmonary laterality defects resulting from an abnormal Nodal->Pitx2c pathway. Here we show that a maternal high-fat diet more than doubles the penetrance of laterality defects and, surprisingly, induces palatal clefting in Cited2-deficient embryos. Both maternal diet and Cited2 deletion reduce embryo weight and kidney and thymus volume. Expression profiling identified 40 embryonic transcripts including Pitx2 that were significantly affected by embryonic genotype-maternal diet interaction. We show that a high-fat diet reduces Pitx2c levels >2-fold in Cited2-deficient embryos. Taken together, these results define a novel interaction between maternal high-fat diet and embryonic Cited2 deficiency that affects Pitx2c expression and results in abnormal laterality. They suggest that appropriate modifications of maternal diet may prevent such defects in humans.
转录因子 Cited2 缺失的小鼠会导致心脏畸形、肾上腺发育不全、神经管、胎盘缺陷以及部分穿透性心肺侧位缺陷，这是由于异常的 Nodal->Pitx2c 途径引起的。在这里，我们表明，母体高脂肪饮食使侧位缺陷的外显率增加了一倍以上，并且令人惊讶的是，还会诱导 Cited2 缺失胚胎的腭裂。母体饮食和 Cited2 缺失都会降低胚胎体重以及肾脏和胸腺体积。表达谱分析确定了 40 个胚胎转录本，包括受胚胎基因型-母体饮食相互作用显著影响的 Pitx2。我们表明，高脂肪饮食使 Cited2 缺失胚胎中的 Pitx2c 水平降低了 >2 倍。总之，这些结果定义了母体高脂肪饮食与胚胎 Cited2 缺失之间的一种新的相互作用，这种相互作用会影响 Pitx2c 的表达并导致异常的侧位。它们表明适当调整母体饮食可能会预防此类人类缺陷。
