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MicroRNA‐122 (miR‐122) Regulates Postnatal Polyploidization in the Murine Liver
Author(s) -
Hsu Shuhao,
Otero Anthony,
Meehan Kolin,
Duncan Andrew
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.lb422
Subject(s) - biology , cytokinesis , microrna , microbiology and biotechnology , polyploid , genetics , ploidy , cell division , cell , gene
A defining feature of the mammalian liver is polyploidy, a numerical change in the complement of chromosomes. Hepatocytes are either mono‐ or binucleate, and ploidy is determined by the number of nuclei/cell, as well as the ploidy of each nucleus. The first step of polyploidization involves cell division with failed cytokinesis. Polyploidy is common, affecting ~90% of hepatocytes in mice and 50% in humans, but the specialized role played by polyploid cells in liver homeostasis and disease remains poorly understood. The goal of this study was to identify signals that regulate polyploidization, and we focused on microRNAs (miRNAs). First, to test whether miRNAs could regulate hepatic polyploidy we examined livers from Dicer1 ‐/‐ mice, which are devoid of mature miRNAs. Loss of miRNAs resulted in a 3‐fold reduction in binucleate hepatocytes, indicating that miRNAs could indeed regulate polyploidization. Secondly, we surveyed age‐dependent expression of >500 miRNAs (NanoString) in wild type mice and identified a subset of miRNAs, including miR‐122, differentially expressed at 2‐3 weeks, a period when extensive polyploidization occurs. Next, we examined Mir122 ‐/‐ mice and observed profound, life‐long depletion of polyploid hepatocytes, proving that miR‐122 is required for complete hepatic polyploidization. Finally, we showed that miR‐122 antagonizes pro‐cytokinesis genes, Iqgap1 , Mapre1 , Nedd4l and Slc25a34 , which promoted cytokinesis failure and emergence of binucleate, polyploid hepatocytes. In summary, our data suggest a novel regulatory role for miR‐122 in liver polyploidization. These studies will serve as the foundation for future work investigating miR‐122 and polyploidy in liver diseases. Support provided to AWD from the NIH (R01DK103645) and Commonwealth of PA.