The distal nephron and collecting duct segments of the mammalian kidney consist of intercalated cell types intermingled among principal cell types. Notch signaling ensures that a sufficient number of cells select a principal instead of an intercalated cell fate. However, the precise mechanisms by which Notch signaling patterns the distal nephron and collecting duct cell fates is unknown. Here we observed that Hes1, a direct target of Notch signaling pathway, is required within the mouse developing collecting ducts for repression of Foxi1 expression, an essential intercalated cell specific transcription factor. Interestingly, inactivation of Foxi1 in Hes1-deficient collecting ducts rescues the deficiency in principal cell fate selection, overall urine concentrating deficiency, and reduces the occurrence of hydronephrosis. However, Foxi1 inactivation does not rescue the reduction in expression of all principal cell genes in the Hes1-deficient kidney collecting duct cells that select the principal cell fate. Additionally, suppression of Notch/Hes1 signaling in mature principal cells reduces principal cell gene expression without activating Foxi1. We conclude that Hes1 is a Notch signaling target that is essential for normal patterning of the collecting ducts with intermingled cell types by repressing Foxi1, and for maintenance of principal cell gene expression independent of repressing Foxi1.

哺乳动物肾脏的远端肾单位和集合管段由主要细胞类型之间混合的嵌入细胞类型组成。Notch 信号确保足够数量的细胞选择主体而不是插入的细胞命运。然而，Notch 信号传导模式远端肾单位和集合管细胞命运的确切机制尚不清楚。在这里，我们观察到Hes1， Notch 信号通路的直接目标，在小鼠发育收集管中是必需的，以抑制Foxi1表达，这是一种必不可少的嵌入细胞特异性转录因子。有趣的是，灭活FOXI1在Hes1基因- 集合管缺陷可挽救主细胞命运选择缺陷、整体尿液浓缩缺陷，减少肾积水的发生。然而，Foxi1失活并不能挽救 Hes1 缺陷肾集合管细胞中所有主细胞基因表达的减少，这些细胞选择主细胞命运。此外，成熟主细胞中 Notch/Hes1 信号传导的抑制降低了主细胞基因表达而不激活Foxi1。我们得出结论，Hes1 是一个 Notch 信号靶标，它对于通过抑制Foxi1 使具有混合细胞类型的集合管的正常模式形成以及维持独立于抑制Foxi1的主细胞基因表达至关重要。.