Epithelial Carcinogenesis Group, Molecular Pathology Programme, CNIO-Spanish National Cancer Research Centre, Madrid, Spain.
Gut. 2013 Oct;62(10):1481-8. doi: 10.1136/gutjnl-2012-303328. Epub 2012 Sep 21.
Previous studies have suggested an important role of the transcription factor Gata6 in endocrine pancreas, while GATA6 haploinsufficient inactivating mutations cause pancreatic agenesis in humans. We aimed to analyse the effects of Gata6 inactivation on pancreas development and function.
We deleted Gata6 in all epithelial cells in the murine pancreas at the onset of its development. Acinar proliferation, apoptosis, differentiation and exocrine functions were assessed using reverse transcriptase quantitative PCR (RT-qPCR), chromatin immunoprecipitation, immunohistochemistry and enzyme assays. Adipocyte transdifferentiation was assessed using electron microscopy and genetic lineage tracing.
Gata6 is expressed in all epithelial cells in the adult mouse pancreas but it is only essential for exocrine pancreas homeostasis: while dispensable for pancreatic development after e10.5, it is required for complete acinar differentiation, for establishment of polarity and for the maintenance of acinar cells in the adult. Gata6 regulates directly the promoter of genes coding for digestive enzymes and the transcription factors Rbpjl and Mist1. Upon pancreas-selective Gata6 inactivation, massive loss of acinar cells and fat replacement take place. This is accompanied by increased acinar apoptosis and proliferation, acinar-to-ductal metaplasia and adipocyte transdifferentiation. By contrast, the endocrine pancreas is spared.
Our data show that Gata6 is required for the complete differentiation of acinar cells through multiple transcriptional regulatory mechanisms. In addition, it is required for the maintenance of the adult acinar cell compartment. Our studies suggest that GATA6 alterations may contribute to diseases of the human adult exocrine pancreas.
先前的研究表明转录因子 Gata6 在内分泌胰腺中具有重要作用，而 GATA6 杂合失活突变会导致人类胰腺发育不全。我们旨在分析 Gata6 失活对胰腺发育和功能的影响。
我们在胰腺发育开始时在所有上皮细胞中敲除了 Gata6。使用逆转录定量 PCR（RT-qPCR）、染色质免疫沉淀、免疫组织化学和酶测定评估了腺泡增殖、凋亡、分化和外分泌功能。使用电子显微镜和遗传谱系追踪评估了脂肪细胞转分化。
Gata6 在成年小鼠胰腺的所有上皮细胞中表达，但仅对外分泌胰腺的稳态至关重要：尽管在 e10.5 后对胰腺发育不是必需的，但它是完全腺泡分化、建立极性和维持成年腺泡细胞所必需的。Gata6 直接调节编码消化酶和转录因子 Rbpjl 和 Mist1 的基因的启动子。在胰腺选择性 Gata6 失活后，大量的腺泡细胞丢失和脂肪替代发生。这伴随着腺泡细胞凋亡和增殖增加、腺泡到导管的化生和脂肪细胞转分化。相比之下，内分泌胰腺则幸免。
我们的数据表明，Gata6 通过多种转录调控机制，对腺泡细胞的完全分化是必需的。此外，它对成年腺泡细胞区室的维持是必需的。我们的研究表明，GATA6 的改变可能会导致人类外分泌胰腺疾病。
