Circadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway

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.

<b>Circadian rhythms of micturition during jet </b><b>lag </b>

“…2B, lower panel). In Per-null mice whose circadian clock is completely disrupted, locomotor activity was high in the night time, and low in the day time as reported previously (2). Similarly, the micturition frequency and void volume of micturition of Per-null mice showed temporal variation under LD cycles (Figs.…”

Population Dynamics and Neuronal Polyploidy in the Developing Neocortex

“…To test whether 4C neurons could be polyploid, we first confirmed that our flow cytometry pipeline is efficient at detecting polyploid cells by processing adult liver tissues as positive controls. The flow cytometry pipeline was able to detect polyploid cells in the liver, with a higher accumulation in older tissues as expected (Chao et al, 2017) (Sup Figure 5A, B).…”

Hyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver

“…Using glutamine synthetase (GS) expression as marker for CL hepatocytes 21 , the central vein to portal vein (CV-PV) axis was subdivided into 15 parts ( Supplementary Fig. 1a), and the sizes of cells and nuclei were quantified along this axis, as described previously 13 . Remarkably, only hepatocytes close to the CL and midlobular (ML) regions displayed enlarged nuclei compared to control liver ( Fig.…”

“…During postnatal development, hepatocytes progressively develop polyploidy 11,13 via incomplete cytokinesis without contractile ring formation, which is the major mechanism for generation of polyploid hepatocytes after weaning 11 . Recently, a population of hepatocytes failing abscission has been identified following the disruption of the Period genes, which was shown to increase abscission failure and accelerate hepatocytes hyperpolyploidization 13 . "Physiological" hepatocyte polyploidization has been proposed as a diversity factor for liver homeostasis, and as a mechanism to restrict proliferation and promote tumor suppression 14,15,16 .…”