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首页> 外文期刊>Biology Open >Introducing Pitt-Hopkins syndrome-associated mutations of TCF4 to Drosophila daughterless
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Introducing Pitt-Hopkins syndrome-associated mutations of TCF4 to Drosophila daughterless

机译：将与皮特-霍普金斯综合征相关的TCF4突变引入无子蝇果蝇

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Pitt-Hopkins syndrome (PTHS) is caused by haploinsufficiency of Transcription factor 4 (TCF4) , one of the three human class I basic helix-loop-helix transcription factors called E-proteins. Drosophila has a single E-protein, Daughterless (Da), homologous to all three mammalian counterparts. Here we show that human TCF4 can rescue Da deficiency during fruit fly nervous system development. Overexpression of Da or TCF4 specifically in adult flies significantly decreases their survival rates, indicating that these factors are crucial even after development has been completed. We generated da transgenic fruit fly strains with corresponding missense mutations R578H, R580W, R582P and A614V found in TCF4 of PTHS patients and studied the impact of these mutations in vivo . Overexpression of wild type Da as well as human TCF4 in progenitor tissues induced ectopic sensory bristles and the rough eye phenotype. By contrast, overexpression of DaR580W and DaR582P that disrupt DNA binding reduced the number of bristles and induced the rough eye phenotype with partial lack of pigmentation, indicating that these act dominant negatively. Compared to the wild type, DaR578H and DaA614V were less potent in induction of ectopic bristles and the rough eye phenotype, respectively, suggesting that these are hypomorphic. All studied PTHS-associated mutations that we introduced into Da led to similar effects in vivo as the same mutations in TCF4 in vitro . Consequently, our Drosophila models of PTHS are applicable for further studies aiming to unravel the molecular mechanisms of this disorder.
机译：皮特-霍普金斯综合征（PTHS）是由转录因子4（TCF4）的单倍缺乏引起的，转录因子4是三种人类I类基本螺旋-环-螺旋转录因子之一，称为E蛋白。果蝇具有单一的E蛋白，无子（Da），与所有三个哺乳动物对应物同源。在这里，我们显示了人类TCF4可以在果蝇神经系统发育过程中挽救Da缺乏症。 Da或TCF4特别是在成年果蝇中过表达会显着降低其存活率，这表明即使在发育完成后，这些因素也至关重要。我们在PTHS患者的TCF4中产生了带有相应错义突变R578H，R580W，R582P和A614V的da转基因果蝇菌株，并研究了这些突变在体内的影响。祖细胞中野生型Da以及人TCF4的过表达诱导了异位感觉性刷毛和粗糙的眼表型。相比之下，破坏DNA结合的DaR580W和DaR582P的过表达减少了刷毛的数量，并诱导了粗糙的眼表型，并部分缺乏色素沉着，表明它们负起显性作用。与野生型相比，DaR578H和DaA614V分别在诱导异位刷毛和粗糙眼表型方面的效力较弱，表明它们是亚型的。我们引入Da的所有研究的与PTHS相关的突变在体内产生的效果与体外TCF4中的相同突变相似。因此，我们的果蝇PTHS模型可用于进一步研究，以阐明该疾病的分子机制。

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