RT Journal Article
SR Electronic
T1 Polarity signaling ensures epidermal homeostasis by coupling cellular mechanics and genomic integrity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 401562
DO 10.1101/401562
A1 Martim Dias Gomes
A1 Soriba Letzian
A1 Michael Saynisch
A1 Sandra Iden
YR 2018
UL http://biorxiv.org/content/early/2018/08/27/401562.abstract
AB 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 actomyosin contractility and viscoelasticity, and elicits 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/ROCK-mediated 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.