| Abstract: |
The ubiquitously expressed nucleoside diphosphate kinases (Nm23/NDPK/Awd) are a large family of multifunctional enzymes implicated in nucleic acid metabolism and in normal and abnormal development. Here, we describe the generation and characterization of NDPK A- and B-deficient (Nme <sup>1-/-</sup>/Nme2<sup>-/-</sup>) mice in which >95% of the enzyme activity is eliminated. These mice are undersized, die perinatally, and exhibit a spectrum of hematological phenotypes including severe anemia, impaired maturation of erythrocytes, and abnormal hematopoiesis in the liver and bone marrow. Flow cytometric analysis of developing Nme1<sup>-/-</sup>/Nme2 <sup>-/-</sup> erythroid cells indicated that the major iron transport receptor molecule TfR1 is attenuated concomitant with a reduction of intracellular iron, suggesting that TfR1 is a downstream target of NDPKs and that reduced iron in Nme1<sup>-/-</sup>/Nme2<sup>-/-</sup> erythroblasts is inhibiting their development. We conclude that Nm23/NDPKs play critical roles in definitive erythroid development. Our novel mouse model also links erythropoiesis and nucleotide metabolism. © 2009 Wiley-Liss, Inc. |
| Keywords: |
protein expression; unclassified drug; gene deletion; nonhuman; flow cytometry; mouse; phenotype; animals; mice; animal tissue; cells, cultured; gene targeting; mus; anemia; bone marrow; cell maturation; erythroblast; erythropoiesis; genotype; enzyme activity; histology; gene expression regulation, developmental; liver; transcription regulation; rna, messenger; iron; erythroid cell; embryo, mammalian; hematopoiesis; erythrocyte; antigens, cd; dna determination; transcriptional regulation; downstream processing; mouse embryo; iron transport; ndp kinase; nm23; nucleoside diphosphate kinase; nucleoside diphosphate kinase a; nucleoside diphosphate kinase b; hematology; nucleic acid metabolism; perinatal death; globins; nm23 nucleoside diphosphate kinases
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