A ROLE FOR CYCLIN D3 IN THE ENDOMITOTIC CELL-CYCLE

Platelets, essential for thrombosis and hemostasis, develop from polyp loid megakaryocytes which undergo endomitosis. During this cell cycle, cells experience abrogated mitosis and reenter a phase of DNA synthes is, thus leading to endomitosis. In the search for regulators of the e ndomitotic cell cycle, se have identified cyclin D3 as an important re gulatory factor. Of the D-type cyclins, cyclin D3 is present at high l evels in megakaryocytes undergoing endomitosis and is markedly upregul ated following exposure to the proliferation-, maturation-, and ploidy -promoting factor, Mpl ligand, Transgenic mice in which cyclin D3 is o verexpressed in the platelet lineage display a striking increase in en domitosis, similar to changes seen following Mpl ligand administration to normal mice. Electron microscopy analysis revealed that unlike suc h treated mice, however, D3 transgenic mice show a poor development of demarcation membranes, from which platelets are believed to fragment, and no increase in platelets. Thus, while our model supports a key ro le for cyclin D3 in the endomitotic cell cycle, it also points to the unique role of Mpl ligand in priming megakaryocytes towards ards plate let fragmentation. The role of cyclin D3 in promoting endomitosis ist other lineages programmed to abrogate mitosis will need further explor ation.