Targeted deletion of Nm23/nucleoside diphosphate kinase A and B reveals their requirement for definitive erythropoiesis in the mouse embryo.
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 (Nme1(-/-)/Nme2(-/-)) 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(-/-)/Nme2(-/-) 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(-/-)/Nme2(-/-) 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.
Postel
Edith H
EH
Laboratory of Biochemistry and Molecular Biology, Department of Pediatrics, Robert Wood Johnson Medical School/UMDNJ and Cancer Institute of New Jersey, Medical Education Building, New Brunswick, New Jersey 08903-0019, USA. posteleh@umdnj.edu
Wohlman
Irene
I
Zou
Xiaoming
X
Juan
Todd
T
Sun
Ning
N
D'Agostin
Diane
D
Cuellar
Maria
M
Choi
Theresa
T
Notterman
Daniel A
DA
La Perle
Krista M D
KM
D000740:Anemia / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000196:embryology* / Q000201:enzymology*; D004920:Erythropoiesis; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D005914:Globins / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000097:blood; D008099:Liver / Q000196:embryology / Q000201:enzymology; D051379:Mice; D054778:NM23 Nucleoside Diphosphate Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics
D015703:Antigens, CD; D054778:NM23 Nucleoside Diphosphate Kinases; D012333:RNA, Messenger; D005914:Globins; D007501:Iron