RRC ID 50014
Author Chao HW, Doi M, Fustin JM, Chen H, Murase K, Maeda Y, Hayashi H, Tanaka R, Sugawa M, Mizukuchi N, Yamaguchi Y, Yasunaga JI, Matsuoka M, Sakai M, Matsumoto M, Hamada S, Okamura H.
Title Circadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway.
Journal Nat Commun
Abstract Liver metabolism undergoes robust circadian oscillations in gene expression and enzymatic activity essential for liver homeostasis, but whether the circadian clock controls homeostatic self-renewal of hepatocytes is unknown. Here we show that hepatocyte polyploidization is markedly accelerated around the central vein, the site of permanent cell self-renewal, in mice deficient in circadian Period genes. In these mice, a massive accumulation of hyperpolyploid mononuclear and binuclear hepatocytes occurs due to impaired mitogen-activated protein kinase phosphatase 1 (Mkp1)-mediated circadian modulation of the extracellular signal-regulated kinase (Erk1/2) activity. Time-lapse imaging of hepatocytes suggests that the reduced activity of Erk1/2 in the midbody during cytokinesis results in abscission failure, leading to polyploidization. Manipulation of Mkp1 phosphatase activity is sufficient to change the ploidy level of hepatocytes. These data provide clear evidence that the Period genes not only orchestrate dynamic changes in metabolic activity, but also regulate homeostatic self-renewal of hepatocytes through Mkp1-Erk1/2 signaling pathway.
Volume 8(1)
Pages 2238
Published 2017-12-21
DOI 10.1038/s41467-017-02207-7
PII 10.1038/s41467-017-02207-7
PMID 29269828
PMC PMC5740157
MeSH Animals Circadian Clocks / genetics Dual Specificity Phosphatase 1 / metabolism* Hepatocytes / cytology Hepatocytes / metabolism* Hepatocytes / pathology Liver / cytology Liver / metabolism* Liver / pathology MAP Kinase Signaling System / physiology* Mice Mice, Knockout Microscopy Period Circadian Proteins / genetics* Polyploidy* Time-Lapse Imaging
IF 12.121
Times Cited 8
DNA material CSII-EF-MCS-IRES-hrGFP (RDB04382)