Carulli Alexis J, Keeley Theresa M, Demitrack Elise S, Chung Jooho, Maillard Ivan, Samuelson Linda C
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
Dev Biol. 2015 Jun 1;402(1):98-108. doi: 10.1016/j.ydbio.2015.03.012. Epub 2015 Mar 30.
The Notch signaling pathway regulates intestinal epithelial cell homeostasis, including stem cell maintenance, progenitor cell proliferation and differentiation. Notch1 and Notch2 receptors are expressed in the epithelium, but individual contributions to these functions are unclear. We used genetic deletion to define receptor roles on stem cell function, cell proliferation/differentiation, and repair after injury. Loss of Notch1 induced a transient secretory cell hyperplasia that spontaneously resolved over time. In contrast, deletion of Notch2 had no secretory cell effect. Compound deletions of Notch1 and Notch2 resulted in a more severe secretory cell hyperplasia than deletion of Notch1 alone. Furthermore, only double deletion of Notch1 and Notch2 decreased cell proliferation, suggesting a low threshold for maintenance of proliferation compared to differentiation. Stem cells were affected by deletion of Notch1, with reduced expression of Olfm4 and fewer LGR5(+) stem cells. Deletion of Notch2 had no apparent affect on stem cell homeostasis. However, we observed impaired crypt regeneration after radiation in both Notch1- and Notch2-deleted intestine, suggesting that higher Notch activity is required post-injury. These findings suggest that Notch1 is the primary receptor regulating intestinal stem cell function and that Notch1 and Notch2 together regulate epithelial cell proliferation, cell fate determination, and post-injury regeneration.
Notch信号通路调节肠道上皮细胞的稳态，包括干细胞维持、祖细胞增殖和分化。Notch1和Notch2受体在上皮中表达，但它们对这些功能的具体贡献尚不清楚。我们利用基因敲除来确定受体在干细胞功能、细胞增殖/分化以及损伤后修复中的作用。Notch1缺失诱导了短暂的分泌细胞增生，随着时间的推移会自发缓解。相比之下，Notch2缺失对分泌细胞没有影响。Notch1和Notch2的复合缺失导致的分泌细胞增生比单独缺失Notch1更严重。此外，只有Notch1和Notch2的双缺失会降低细胞增殖，这表明与分化相比，维持增殖的阈值较低。Notch1缺失会影响干细胞，导致Olfm4表达降低和LGR5(+)干细胞数量减少。Notch2缺失对干细胞稳态没有明显影响。然而，我们观察到在辐射后的Notch1和Notch2缺失的肠道中隐窝再生受损，这表明损伤后需要更高的Notch活性。这些发现表明，Notch1是调节肠道干细胞功能的主要受体，并且Notch1和Notch2共同调节上皮细胞增殖、细胞命运决定和损伤后再生。
