Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany.
Institute of Molecular Biology gGmbH, 55128 Mainz, Germany.
Cells. 2023 May 23;12(11):1452. doi: 10.3390/cells12111452.
Continuous and rapid renewal of the intestinal epithelium depends on intestinal stem cells (ISCs). A large repertoire of transcription factors mediates the correct maintenance and differentiation of ISCs along either absorptive or secretory lineages. In the present study, we addressed the role of TCF7L1, a negative regulator of WNT signalling, in embryonic and adult intestinal epithelium using conditional mouse mutants. We found that TCF7L1 prevents precocious differentiation of the embryonic intestinal epithelial progenitors towards enterocytes and ISCs. We show that deficiency leads to upregulation of the Notch effector resulting in a subsequent loss of embryonic secretory progenitors. In the adult small intestine, TCF7L1 is required for the differentiation of secretory epithelial progenitors along the tuft cell lineage. Furthermore, we show that promotes the differentiation of enteroendocrine D- and L-cells in the anterior small intestine. We conclude that TCF7L1-mediated repression of both Notch and WNT pathways is essential for the correct differentiation of intestinal secretory progenitors.
肠道上皮的连续快速更新依赖于肠道干细胞(ISCs)。大量转录因子介导 ISC 沿着吸收或分泌谱系的正确维持和分化。在本研究中,我们使用条件性小鼠突变体研究了 WNT 信号的负调节剂 TCF7L1 在胚胎和成年肠道上皮中的作用。我们发现 TCF7L1 可防止胚胎肠道上皮祖细胞过早向肠细胞和 ISC 分化。我们表明, 缺失会导致 Notch 效应物 的上调,从而导致胚胎分泌祖细胞的随后丢失。在成年小肠中,TCF7L1 沿微绒毛细胞谱系分化为分泌上皮祖细胞所必需。此外,我们表明, 促进了前小肠中肠内分泌 D 细胞和 L 细胞的分化。我们得出结论,TCF7L1 介导的 Notch 和 WNT 通路的抑制对于肠道分泌祖细胞的正确分化是必不可少的。