Tissue-specific regulation of the mouse Pkhd1 (ARPKD) gene promoter.
Tissue-specific regulation of the mouse Pkhd1 (ARPKD) gene promoter.
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小鼠 Pkhd1 (ARPKD) 基因启动子的组织特异性调控。
DOI：
10.1152/ajprenal.00422.2013
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Igarashi,Peter
中科院分区：
文献类型：
--
作者：
Williams,ScottS;Cobo-Stark,Patricia;Hajarnis,Sachin;Aboudehen,Karam;Shao,Xinli;Richardson,JamesA;Patel,Vishal;Igarashi,Peter
常染色体隐性遗传性多囊肾病是一种遗传性疾病，其特征是肾集合管中形成囊肿和胆道发育不全，由多囊肾和肝病 1 (PKHD1) 基因突变引起。 PKHD1 的表达具有组织特异性并受发育调节。在这里，我们展示了含有小鼠 Pkhd1 近端启动子的 2.0-kb 基因组片段在转基因小鼠中指导 alacZreporter 基因的组织特异性表达。LacZ 在胚胎发育期间开始在肾集合管中表达，但在肾外组织中不表达。 Pkhd1 启动子含有转录因子肝细胞核因子 (HNF)-1β 的结合位点，这是转染细胞中活性所必需的。 HNF-1β 结合位点的突变消除了肾集合管中 thelacZreporter 基因的表达。含有 2.0 kb 启动子和向下游延伸至第二个外显子的 2.7 kb 附加基因组序列的转基因在肾脏、肝内胆管和男性生殖道中表达。该模式与 Pkhd1 的内源表达重叠，并且与 HNF-1β 的表达位点一致。我们得出结论，近端 2.0-kb 启动子足以在体内肾集合管中组织特异性表达 Pkhd1，并且 HNF-1β 是集合管中 Pkhd1 启动子活性所必需的。在肾外组织中表达需要位于外显子 1-2 或基因座其他位置的额外基因组序列。
Autosomal recessive polycystic kidney disease, an inherited disorder characterized by the formation of cysts in renal collecting ducts and biliary dysgenesis, is caused by mutations of the polycystic kidney and hepatic disease 1 (PKHD1) gene. Expression ofPKHD1is tissue specific and developmentally regulated. Here, we show that a 2.0-kb genomic fragment containing the proximal promoter of mousePkhd1directs tissue-specific expression of alacZreporter gene in transgenic mice.LacZis expressed in renal collecting ducts beginning during embryonic development but is not expressed in extrarenal tissues. ThePkhd1promoter contains a binding site for the transcription factor hepatocyte nuclear factor (HNF)-1β, which is required for activity in transfected cells. Mutation of the HNF-1β-binding site abolishes the expression of thelacZreporter gene in renal collecting ducts. Transgenes containing the 2.0-kb promoter and 2.7 kb of additional genomic sequence extending downstream to the second exon are expressed in the kidney, intrahepatic bile ducts, and male reproductive tract. This pattern overlaps with the endogenous expression ofPkhd1and coincides with sites of expression of HNF-1β. We conclude that the proximal 2.0-kb promoter is sufficient for tissue-specific expression ofPkhd1in renal collecting ducts in vivo and that HNF-1β is required forPkhd1promoter activity in collecting ducts. Additional genomic sequences located from exons 1-2 or elsewhere in the gene locus are required for expression in extrarenal tissues.
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影响因子：
19.6
作者：
Menezes, LFC;Cai, YQ;Onuchic, LF
通讯作者：
Onuchic, LF
影响因子：
13.6
作者：
Hogan, Marie C.;Manganelli, Luca;Ward, Christopher J.
通讯作者：
Ward, Christopher J.
影响因子：
19.6
作者：
Woollard, J. R.;Punyashtiti, R.;Ward, C. J.
通讯作者：
Ward, C. J.
小鼠生殖道中肝细胞核因子 1 的变异表达
影响因子：
2.6
作者：
M. Reber;S. Cereghini
通讯作者：
S. Cereghini
DOI：
10.1097/01.asn.0000016443.50138.cd
发表时间：
2002-07-01
影响因子：
13.6
作者：
Shao, XL;Johnson, JE;Igarashi, P
通讯作者：
Igarashi, P