Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, 50931, Germany.
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, 50931, Germany.
Nat Commun. 2019 Jul 29;10(1):3362. doi: 10.1038/s41467-019-11325-3.
Epithelial homeostasis requires balanced progenitor cell proliferation and differentiation, whereas disrupting this equilibrium fosters degeneration or cancer. Here we studied how cell polarity signaling orchestrates epidermal self-renewal and differentiation. Using genetic ablation, quantitative imaging, mechanochemical reconstitution and atomic force microscopy, we find that mammalian Par3 couples genome integrity and epidermal fate through shaping keratinocyte mechanics, rather than mitotic spindle orientation. Par3 inactivation impairs RhoA activity, actomyosin contractility and viscoelasticity, eliciting mitotic failures that trigger aneuploidy, mitosis-dependent DNA damage responses, p53 stabilization and premature differentiation. Importantly, reconstituting myosin activity is sufficient to restore mitotic fidelity, genome integrity, and balanced differentiation and stratification. Collectively, this study deciphers a mechanical signaling network in which Par3 acts upstream of Rho/actomyosin contractility to promote intrinsic force generation, thereby maintaining mitotic accuracy and cellular fitness at the genomic level. Disturbing this network may compromise not only epidermal homeostasis but potentially also that of other self-renewing epithelia.
上皮组织稳态需要平衡的祖细胞增殖和分化，而破坏这种平衡则会促进退化或癌症。在这里，我们研究了细胞极性信号如何协调表皮自我更新和分化。通过遗传消融、定量成像、力学重组和原子力显微镜，我们发现哺乳动物 Par3 通过塑造角质形成细胞力学，而不是有丝分裂纺锤体方向，将基因组完整性和表皮命运联系起来。Par3 失活会损害 RhoA 活性、肌动球蛋白收缩性和粘弹性，引发有丝分裂失败，导致非整倍体、有丝分裂依赖性 DNA 损伤反应、p53 稳定和过早分化。重要的是，重新构建肌球蛋白活性足以恢复有丝分裂保真度、基因组完整性以及平衡的分化和分层。总的来说，这项研究揭示了一个机械信号网络，其中 Par3 在 Rho/肌动球蛋白收缩性之前起作用，以促进内在力的产生，从而维持基因组水平的有丝分裂准确性和细胞适应性。破坏这个网络不仅可能危及表皮稳态，还可能危及其他自我更新的上皮组织。
