Sallé Jérémy, Gervais Louis, Boumard Benjamin, Stefanutti Marine, Siudeja Katarzyna, Bardin Allison J
Institut Curie, PSL Research University, CNRS UMR 3215, INSERM U934, Stem Cells and Tissue Homeostasis Group, Paris, France.
Sorbonne Universités, UPMC Univ Paris 6, Paris, France.
EMBO J. 2017 Jul 3;36(13):1928-1945. doi: 10.15252/embj.201695622. Epub 2017 May 22.
How terminal cell fates are specified in dynamically renewing adult tissues is not well understood. Here we explore terminal cell fate establishment during homeostasis using the enteroendocrine cells (EEs) of the adult midgut as a paradigm. Our data argue against the existence of local feedback signals, and we identify Numb as an intrinsic regulator of EE fate. Our data further indicate that Numb, with alpha-adaptin, acts upstream or in parallel of known regulators of EE fate to limit Notch signaling, thereby facilitating EE fate acquisition. We find that Numb is regulated in part through its asymmetric and symmetric distribution during stem cell divisions; however, its synthesis is also required during the differentiation of the EE cell. Thus, this work identifies Numb as a crucial factor for cell fate choice in the adult intestine. Furthermore, our findings demonstrate that cell-intrinsic control mechanisms of terminal cell fate acquisition can result in a balanced tissue-wide production of terminally differentiated cell types.
在动态更新的成体组织中，终末细胞命运是如何被指定的，目前还不太清楚。在这里，我们以成年中肠的肠内分泌细胞（EEs）为范例，探索稳态过程中终末细胞命运的建立。我们的数据反驳了局部反馈信号的存在，并且我们确定Numb是EE命运的内在调节因子。我们的数据进一步表明，Numb与α-衔接蛋白一起，在EE命运的已知调节因子上游或与其平行发挥作用，以限制Notch信号传导，从而促进EE命运的获得。我们发现，Numb部分通过其在干细胞分裂过程中的不对称和对称分布受到调节；然而，在EE细胞分化过程中也需要其合成。因此，这项工作确定Numb是成年肠道细胞命运选择的关键因素。此外，我们的研究结果表明，终末细胞命运获得的细胞内在控制机制可以导致终末分化细胞类型在全组织范围内的平衡产生。
