期刊
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
卷 11, 期 2, 页码 503-524出版社
ELSEVIER INC
DOI: 10.1016/j.jcmgh.2020.08.013
关键词
Signaling Crosstalk; Progenitor Cells; Intestinal Homeostasis
资金
- National Institutes of Health [R35 CA197222]
- Washington State Andy Hill CARE Fund
- Japan Society for the Promotion of Science Overseas Research Fellowships [JSPS 201860777]
The study revealed that activation of the Nrf2 signaling negatively regulates Math1 in the Notch cascade, leading to excessive enterogenesis in the intestinal epithelium. These two signaling pathways have inverse spatial profiles in the intestinal epithelium, and may play crucial roles in regulating intestinal homeostasis.
BACKGROUND & AIMS: Notch signaling coordinates cell differentiation processes in the intestinal epithelium. The transcription factor Nrf2 orchestrates defense mechanisms by regulating cellular redox homeostasis, which, as shown previously in murine liver, can be amplified through signaling crosstalk with the Notch pathway. However, interplay between these 2 signaling pathways in the gut is unknown. METHODS: Mice modified genetically to amplify Nrf2 in the intestinal epithelium (Keap1(f/f)::VilCre) were generated as well as pharmacological activation of Nrf2 and subjected to phenotypic and cell lineage analyses. Cell lines were used for reporter gene assays together with Nrf2 overexpression to study transcriptional regulation of the Notch downstream effector. RESULTS: Constitutive activation of Nrf2 signaling caused increased intestinal length along with expanded cell number and thickness of enterocytes without any alterations of secretory lineage, outcomes abrogated by concomitant disruption of Nrf2. The Nrf2 and Notch pathways in epithelium showed inverse spatial profiles, where Nrf2 activity in crypts was lower than villi. In progenitor cells of Keap1(f/f)::VilCre mice, Notch downstream effector Math1, which regulates a differentiation balance of cell lineage through lateral inhibition, showed suppressed expression. In vitro results demonstrated Nrf2 negatively regulated Math1, where 6 antioxidant response elements located in the regulatory regions contributed to this repression. CONCLUSIONS: Activation of Nrf2 perturbed the dialog of the Notch cascade though negative regulation of Math1 in progenitor cells, leading to enhanced enterogenesis. The crosstalk between the Nrf2 and Notch pathways could be critical for fine-tuning intestinal homeostasis and point to new approaches for the pharmacological management of absorptive deficiencies.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据