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Papers In Press, published online ahead of print March 7, 2003
INSERM U370, Paris 75015
Corresponding Author: desdouet{at}necker.fr
Polyploidy is a general physiological process indicative of terminal differentiation. During liver growth, this process generates the appearance of tetraploid and octoploid hepatocytes with one or two nuclei. The onset of polyploidy in the liver has been recognized for quite some time; however, the cellular mechanisms which govern it remain unknown. In this report, we observed the sequential appearance during liver growth of binuclear 2x2n and mononuclear 4n hepatocytes from a diploid hepatocyte population. In order to identify the cell cycle modifications involved in hepatocyte polyploidization, mitosis was then monitored in primary cultures of rat hepatocytes. Twenty percent of mononuclear 2n hepatocytes failed to undergo cytokinesis, with no observable contractile movement of the ring. This process led to the formation of binuclear 2x2n hepatocytes. This tetraploid condition following cleavage failure did not activate the p53-dependent checkpoint in G1. In fact, binuclear hepatocytes were able to proceed through S phase and the formation of a bipolar spindle during mitosis constituted the key step leading to the genesis of two mononuclear 4n hepatocytes. Finally, we studied the duplication and clustering of centrosomes in the binuclear hepatocyte. These cells exhibited two centrosomes in G1 which were duplicated during S phase, and then clustered by pairs at opposite poles of the cell during metaphase. This event led only to mononuclear 4n progeny and maintained the tetraploidy status of hepatocytes.
J. Biol. Chem, 10.1074/jbc.M300982200
Submitted on January 29, 2003
Revised on March 6, 2003
Accepted on March 7, 2003
Liver cell polyploidization: A pivotal role for binuclear hepatocytes
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