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Requirement of DNase II for Definitive Erythropoiesis in the Mouse Fetal Liver




Mature erythrocytes in mammals have no nuclei, although they differentiate from nucleated precursor cells. The mechanism by which enucleation occurs is not well understood. Here we show that DNase II is indispensable for definitive erythropoiesis in mouse fetal liver. No live DNase II-null mice were born due to severe anemia. When mutant fetal liver cells were transferred into lethally irradiated wild-type mice, mature red blood cells were generated from the mutant cells, suggesting that DNase II functions in a non-cell autonomous manner. Histochemical analyses indicated that the critical cellular sources of DNase II are macrophages present at the site of definitive erythropoiesis in the fetal liver. Thus, DNase II in macrophages appears to be responsible for destroying the nuclear DNA expelled from erythroid precursor cells.


Apoptosis, often accompanied by the fragmentation of chromosomal DNA, is a physiological cell death process that removes toxic or harmful cells from our bodies (1). This process is triggered by a variety of stimuli such as death factor, anti-cancer drugs and factor-deprivation (2), and is mediated by a family of proteases called caspases (3), and a specific DNase (CAD, caspase-activated DNase)(4). We previously showed that the apoptotic DNA fragmentation can occur not only by CAD in dying cells but also by an enzyme in macrophages after apoptotic cells are phagocytosed (5). DNase II is an acid DNase localized in the lysosomes (6), suggesting that DNase II is involved in apoptotic DNA degradation. To investigate this possibility and explore the physiological roles of DNase II, we generated mice deficient in the DNase II gene, and found an unexpected role of this enzyme in production of red blood cells.


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