Ye Diana Z, Kaestner Klaus H
Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Gastroenterology. 2009 Dec;137(6):2052-62. doi: 10.1053/j.gastro.2009.08.059. Epub 2009 Sep 6.
BACKGROUND & AIMS: The winged helix transcription factors Foxa1 and Foxa2 are expressed in all epithelia of the gastrointestinal tract from its embryonic origin into adulthood. In vitro studies have shown that Foxa1/a2 can transactivate the promoters of Mucin 2 (Muc2), which is expressed in goblet cells, and of preproglucagon, which is expressed in enteroendocrine cells. These findings suggest Foxa1/a2 as critical factors in the differentiation of gut epithelial cells.
Mice with intestine-specific simultaneous deletion of Foxa1 and Foxa2 were derived using the Cre-loxP system and analyzed using histologic and molecular means.
Both Foxa1 and Foxa2 were deleted successfully in the epithelia of the small intestine and colon using Villin-Cre mice. Immunohistochemical staining showed that Foxa1/a2 mutants lack glucagon-like peptide-1- and peptide-2-expressing cells (L-cells), and have reduced numbers of somatostatin (D-cells) and peptide YY-expressing cells (L-cells). Preproglucagon, somatostatin, and peptide YY messenger RNA (mRNA) levels also were reduced significantly in Foxa1/a2 mutants. Thus, Foxa1 and Foxa2 are essential regulators of these enteroendocrine lineages in vivo. The mRNA levels of transcription factors Islet-1 and Pax6 were reduced significantly in the small intestine, showing that Foxa1 and Foxa2 impact on a transcription factor network in the enteroendocrine lineage. In addition, deletion of Foxa1/a2 caused a reduction in goblet cell number with altered expression of the secretory mucins Muc2, Mucin5b, Mucin5ac, and Mucin 6.
The winged helix factors Foxa1 and Foxa2 are essential members of the transcription factor network that govern secretory cell differentiation in the mammalian gastrointestinal tract.
翼状螺旋转录因子Foxa1和Foxa2在胃肠道从胚胎起源到成年期的所有上皮细胞中均有表达。体外研究表明，Foxa1/a2可反式激活在杯状细胞中表达的黏蛋白2（Muc2）以及在肠内分泌细胞中表达的前胰高血糖素原的启动子。这些发现表明Foxa1/a2是肠道上皮细胞分化中的关键因子。
利用Cre-loxP系统构建肠道特异性同时缺失Foxa1和Foxa2的小鼠，并采用组织学和分子学方法进行分析。
使用绒毛蛋白-Cre小鼠成功在小肠和结肠上皮细胞中删除了Foxa1和Foxa2。免疫组织化学染色显示，Foxa1/a2突变体缺乏表达胰高血糖素样肽-1和肽-2的细胞（L细胞），并且表达生长抑素的细胞（D细胞）和表达肽YY的细胞（L细胞）数量减少。Foxa1/a2突变体中前胰高血糖素原、生长抑素和肽YY信使核糖核酸（mRNA）水平也显著降低。因此，Foxa1和Foxa2是体内这些肠内分泌谱系的重要调节因子。小肠中转录因子胰岛-1和Pax6的mRNA水平显著降低，表明Foxa1和Foxa2影响肠内分泌谱系中的转录因子网络。此外，删除Foxa1/a2导致杯状细胞数量减少，同时分泌性黏蛋白Muc2、黏蛋白5b、黏蛋白5ac和黏蛋白6的表达发生改变。
翼状螺旋因子Foxa1和Foxa2是调控哺乳动物胃肠道分泌细胞分化的转录因子网络的重要成员。
