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首页> 外文期刊>Cell and Tissue Research >Gene regulation by homeobox transcription factor Prox1 in murine hepatoblasts
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Gene regulation by homeobox transcription factor Prox1 in murine hepatoblasts

机译：同源盒转录因子Prox1在鼠成肝细胞中的基因调控。

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摘要

The homeobox transcription factor Prox1 is expressed in embryonic hepatoblasts and remains expressed in adult hepatocytes. Prox1-null mice show severe deficiencies in liver development, although the underlying mechanisms are unknown. We have studied the effects of Prox1 on the transcriptional profile of met-murine hepatocytes (MMH) obtained on embryonic day 14 (ED14). These immortalized murine hepatoblasts express numerous hepatoblast markers, but not Prox1. We have performed stable transfection with Prox1 cDNA, analyzed the transcriptome with Agilent mouse whole-genome microarrays, and validated genes by quantitative reverse transcription/polymerase chain reaction. We have observed the up-regulation of 22 genes and the down-regulation of 232 genes, by more than 12-fold. Many of these genes are involved in metabolic hepatocyte functions and may be regulated by Prox1 directly or indirectly, e.g., by the down-regulation of hepatocyte nuclear factor 4α. Prox1 induces the down-regulation of transcription factors that are highly expressed in neighboring endodermal organs, suggesting a function during hepatoblast commitment. Prox1 does not influence the proliferative activity of MMH but regulates genes involved in liver morphogenesis. We have observed the up-regulation of both type-IVα3 procollagen and functionally active matrix metalloproteinase-2 (MMP-2), an observation that places Prox1 at the center of liver matrix turnover. This is consistent with MMP-2 expression in hepatoblasts during liver development and with the persistence of a basal lamina around the liver bud in Prox1-deficient mice. Our studies suggest that Prox1 is a multifunctional regulator of liver morphogenesis and of hepatocyte function and commitment.
机译：同源盒转录因子Prox1在胚胎成肝细胞中表达，并在成人肝细胞中表达。 Prox1 null小鼠显示出严重的肝脏发育缺陷，尽管其潜在机制尚不清楚。我们已经研究了Prox1对在胚胎第14天（ED14）获得的鼠科动物肝细胞（MMH）转录谱的影响。这些永生化的鼠类成肝细胞表达大量成肝细胞标记物，但不表达Prox1。我们已经用Prox1 cDNA进行了稳定的转染，使用安捷伦小鼠全基因组微阵列分析了转录组，并通过定量逆转录/聚合酶链反应验证了基因。我们已经观察到22个基因的上调和232个基因的下调超过12倍。这些基因中的许多都参与了代谢性肝细胞的功能，并可能被Prox1直接或间接地调控，例如，通过肝细胞核因子4α的下调。 Prox1诱导在邻近的内胚层器官中高度表达的转录因子的下调，提示在成肝细胞定型过程中发挥功能。 Prox1不会影响MMH的增殖活性，但会调节参与肝形态发生的基因。我们已经观察到IVα3型胶原蛋白和功能性活性基质金属蛋白酶-2（MMP-2）的上调，这一发现将Prox1置于肝脏基质更新的中心。这与肝脏发育过程中成肝细胞中MMP-2的表达以及Prox1缺陷小鼠肝芽周围基底层的持续存在是一致的。我们的研究表明，Prox1是肝形态发生以及肝细胞功能和作用的多功能调节剂。

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