Notch信号通路调节胃肠干细胞增殖和分化，然而，胃上皮细胞分化的Notch调控转录效应子尚不明确。本研究测试了bHLH转录因子achaete-scute homolog 1（ASCL1）在胃上皮细胞分化中的作用及其被Notch调控的情况。新生Ascl1零基因小鼠显示了与neurogenin-3依赖性enteroendocrine细胞标记物的表达丧失相关，而enterochromaffin样细胞、粘液细胞、主要细胞和壁细胞的表达正常。在成年小鼠中，Ascl1基因表达观察到在胃中，但不在肠中，在幽门部较胃体上皮中表达更高。在Ascl1-CreERT2；Rosa26-LSL-tdTomato小鼠中进行谱系追踪显示，胃上皮中有分散的单个ASCL1阳性细胞，并在幽门部表达胃泌素和血清素产生的内分泌细胞中表达。ASCL1表达的内分泌细胞在tamoxifen标记后持续存在数周，其半衰期约为2个月。在Gastrin-CreERT2小鼠中进行谱系追踪表明，胃泌素产生细胞的寿命类似，证实胃内分泌细胞具有较长的寿命。最后，用泛Notch抑制剂dibenzazepine处理Ascl1-CreERT2；Rosa26-LSL-tdTomato小鼠，可增加胃幽门部谱系标记细胞的数量，提示Notch信号通路通常抑制Ascl1表达。在Notch激活的基因小鼠模型以及经Notch干预的胃幽门部器官培养中，也证明了Notch对Ascl1的调控，从而表明ASCL1是胃上皮中促进内分泌细胞分化的关键下游Notch通路效应子。

Notch signaling regulates gastrointestinal stem cell proliferation and differentiation yet Notch-regulated transcriptional effectors of gastric epithelial cell differentiation are poorly understood. Here we tested the role of the bHLH transcription factor achaete-scute homolog 1 (ASCL1) in gastric epithelial cell differentiation, and its regulation by Notch. Newborn Ascl1 null mice showed a loss of expression of markers of neurogenin-3 dependent enteroendocrine cells, with normal expression of enterochromaffin-like cells, mucous cells, chief cells, and parietal cells. In adult mice, Ascl1 gene expression was observed in stomach, but not intestine, with higher expression in antral than corpus epithelium. Lineage tracing in Ascl1-CreERT2; Rosa26-LSL-tdTomato mice revealed single, scattered ASCL1+ cells in the gastric epithelium, with expression in antral gastrin- and serotonin-producing endocrine cells. ASCL1-expressing endocrine cells persisted for several weeks post-tamoxifen labeling with a half-life of approximately 2 months. Lineage tracing in Gastrin-CreERT2 mice demonstrated a similar lifespan for gastrin-producing cells, confirming that gastric endocrine cells are long-lived. Finally, treatment of Ascl1-CreERT2; Rosa26-LSL-tdTomato mice with the pan-Notch inhibitor dibenzazepine increased the number of lineage-labeledcells in the gastric antrum, suggesting that Notch signaling normally inhibits Ascl1 expression. Notch regulation of Ascl1 was also demonstrated in a genetic mouse model of Notch activation, as well as Notch-manipulated antral organoid cultures, thus suggesting that ASCL1 is a key downstream Notch pathway effector promoting endocrine cell differentiation in the gastric epithelium.