hnf1 - β转录因子有几个区域参与肾脏发生,并部分挽救Pax8/lim1诱导的肾脏畸形。

Guizhi Wu, Silvia Bohn, Gerhart U Ryffel
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引用次数: 40

摘要

组织特异性转录因子hnf1 α和hnf1 β是在脊椎动物进化中保守的密切相关的同源结构域蛋白。人类hnf1 β基因的杂合突变与肾脏畸形有关,但与hnf1 α基因无关。在爪蟾胚胎中过表达hnf1 β会导致原肾发育缺陷,而hnf1 α则没有影响。我们已经确定了在转染的HeLa细胞和注射的爪蟾胚胎中导致hnf1 β和hnf1 α功能差异的区域。通过结构域交换实验,我们在hnf1 β的POUH结构域定位了一个核定位信号,并发现hnf1 β的POUH结构域和POUH结构域在转染细胞中介导了高的转激活电位。在注射的爪蟾胚胎中,有三个hnf1 - β结构域参与肾形成。这些包括二聚化结构域,剪接变体A特有的26个氨基酸片段以及POUH结构域。由于hnf1 β与Pax8和lim1共同构成肾原组织中最早的调节因子,它们可能在早期肾形成过程中相互合作。我们在这里已经证明,hnf1 β可以克服Pax8和lim1过表达介导的异位原肾细胞的扩增和诱导。然而,Pax8和lim1过表达诱导的以囊肿样结构和肾原小管增厚为特征的表型未被hnf1 β过表达改变。综上所述,hnf1 β仅在肾形成过程中的某些过程中对Pax8和lim1起拮抗作用,简单的拮抗关系并不能完全描述这些基因的功能。我们得出结论,hnf1 β在肾发生过程中具有一些独特的形态发生特性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The HNF1beta transcription factor has several domains involved in nephrogenesis and partially rescues Pax8/lim1-induced kidney malformations.

The tissue-specific transcription factors HNF1alpha and HNF1beta are closely related homeodomain proteins conserved in vertebrate evolution. Heterozygous mutations in human HNF1beta but not in HNF1alpha genes are associated with kidney malformations. Overexpression of HNF1beta in Xenopus embryos leads to defective pronephros development, while HNF1alpha has no effect. We have defined the regions responsible for this functional difference between HNF1beta and HNF1alpha in transfected HeLa cells as well as in injected Xenopus embryos. Using domain swapping experiments, we located a nuclear localization signal in the POUH domain of HNF1beta, and showed that the POUS and POUH domains of HNF1beta mediate a high transactivation potential in transfected cells. In injected Xenopus embryos three HNF1beta domains are involved in nephrogenesis. These include the dimerization domain, the 26 amino acid segment specific for splice variant A as well as the POUH domain. As HNF1beta together with Pax8 and lim1 constitute the earliest regulators in the pronephric anlage, it is possible that they cooperate during early nephrogenesis. We have shown here that HNF1beta can overcome the enlargement and the induction of an ectopic pronephros mediated by overexpression of Pax8 and lim1. However, the phenotype induced by Pax8 and lim1 overexpression and characterized by cyst-like structures and thickening of the pronephric tubules was not altered by HNF1beta overexpression. Taken together, HNF1beta acts antagonistically to Pax8 and lim1 in only some processes during nephrogenesis, and a simple antagonistic relationship does not completely describe the functions of these genes. We conclude that HNF1beta has some distinct morphogenetic properties during nephrogenesis.

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