Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Sevilla, Spain.
J Clin Invest. 2012 Oct;122(10):3504-15. doi: 10.1172/JCI63240. Epub 2012 Sep 24.
Recently, heterozygous mutations in GATA6 have been found in neonatal diabetic patients with failed pancreatic organogenesis. To investigate the roles of GATA4 and GATA6 in mouse pancreas organogenesis, we conditionally inactivated these genes within the pancreas. Single inactivation of either gene did not have a major impact on pancreas formation, indicating functional redundancy. However, double Gata4/Gata6 mutant mice failed to develop pancreata, died shortly after birth, and displayed hyperglycemia. Morphological defects in Gata4/Gata6 mutant pancreata were apparent during embryonic development, and the epithelium failed to expand as a result of defects in cell proliferation and differentiation. The number of multipotent pancreatic progenitors, including PDX1+ cells, was reduced in the Gata4/Gata6 mutant pancreatic epithelium. Remarkably, deletion of only 1 Gata6 allele on a Gata4 conditional knockout background severely reduced pancreatic mass. In contrast, a single WT allele of Gata4 in Gata6 conditional knockout mice was sufficient for normal pancreatic development, indicating differential contributions of GATA factors to pancreas formation. Our results place GATA factors at the top of the transcriptional network hierarchy controlling pancreas organogenesis.
最近，在胰腺器官发生失败的新生儿糖尿病患者中发现 GATA6 杂合突变。为了研究 GATA4 和 GATA6 在小鼠胰腺器官发生中的作用，我们在胰腺中条件性地使这些基因失活。单个基因的失活对胰腺形成没有重大影响，表明存在功能冗余。然而，双 Gata4/Gata6 突变小鼠未能发育出胰腺，出生后不久死亡，并表现出高血糖。Gata4/Gata6 突变胰腺的形态缺陷在胚胎发育期间明显，上皮细胞由于细胞增殖和分化缺陷而无法扩张。多能胰腺祖细胞的数量减少，包括 PDX1+细胞，在 Gata4/Gata6 突变胰腺上皮细胞中。值得注意的是，在 Gata4 条件性敲除背景下仅删除 1 个 Gata6 等位基因就严重降低了胰腺质量。相比之下，在 Gata6 条件性敲除小鼠中 Gata4 的单个 WT 等位基因足以正常发育胰腺，表明 GATA 因子对胰腺形成有不同的贡献。我们的结果将 GATA 因子置于控制胰腺器官发生的转录网络层次结构的顶端。
