Cheng Eric, Lu Ran, Gerhold Abigail R
Department of Biology, McGill University, Montréal, Canada.
PLoS Genet. 2024 Dec 23;20(12):e1011351. doi: 10.1371/journal.pgen.1011351. eCollection 2024 Dec.
Stem and progenitor cell mitosis is essential for tissue development and homeostasis. How these cells ensure proper chromosome segregation, and thereby maintain mitotic fidelity, in the complex physiological environment of a living animal is poorly understood. Here we use in situ live-cell imaging of C. elegans germline stem and progenitor cells (GSPCs) to ask how the signaling environment influences stem and progenitor cell mitosis in vivo. Through a candidate screen we identify a new role for the insulin/IGF receptor (IGFR), daf-2, during GSPC mitosis. Mitosis is delayed in daf-2/IGFR mutants, and these delays require canonical, DAF-2/IGFR to DAF-16/FoxO insulin signaling, here acting cell non-autonomously from the soma. Interestingly, mitotic delays in daf-2/IGFR mutants depend on the spindle assembly checkpoint but are not accompanied by a loss of mitotic fidelity. Correspondingly, we show that caloric restriction, which delays GSPC mitosis and compromises mitotic fidelity, does not act via the canonical insulin signaling pathway, and instead requires AMP-activated kinase (AMPK). Together this work demonstrates that GSPC mitosis is influenced by at least two genetically separable signaling pathways and highlights the importance of signaling networks for proper stem and progenitor cell mitosis in vivo.
干细胞和祖细胞的有丝分裂对于组织发育和体内平衡至关重要。在活体动物复杂的生理环境中，这些细胞如何确保正确的染色体分离，从而维持有丝分裂的准确性，目前还知之甚少。在这里，我们利用秀丽隐杆线虫生殖系干细胞和祖细胞（GSPCs）的原位活细胞成像技术，来探究信号环境如何在体内影响干细胞和祖细胞的有丝分裂。通过候选筛选，我们确定了胰岛素/IGF受体（IGFR）daf-2在GSPC有丝分裂过程中的新作用。在daf-2/IGFR突变体中，有丝分裂延迟，并且这些延迟需要经典的从DAF-2/IGFR到DAF-16/FoxO的胰岛素信号传导，这里该信号从体细胞非自主地起作用。有趣的是，daf-2/IGFR突变体中的有丝分裂延迟依赖于纺锤体组装检查点，但并不伴随着有丝分裂准确性的丧失。相应地，我们表明热量限制会延迟GSPC有丝分裂并损害有丝分裂准确性，其作用不是通过经典的胰岛素信号通路，而是需要AMP激活的蛋白激酶（AMPK）。这项工作共同表明，GSPC有丝分裂受到至少两条遗传上可分离的信号通路的影响，并突出了信号网络对于体内干细胞和祖细胞正确有丝分裂的重要性。
