title: Targeted deletion of Nm23/nucleoside diphosphate kinase A and B reveals their requirement for definitive erythropoiesis in the mouse embryo.
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 (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.
authors.affiliation: 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
authors.forename: Edith H
authors.initials: EH
authors.lastname: Postel
authors.forename: Irene
authors.initials: I
authors.lastname: Wohlman
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zou
authors.forename: Todd
authors.initials: T
authors.lastname: Juan
authors.forename: Ning
authors.initials: N
authors.lastname: Sun
authors.forename: Diane
authors.initials: D
authors.lastname: D'Agostin
authors.forename: Maria
authors.initials: M
authors.lastname: Cuellar
authors.forename: Theresa
authors.initials: T
authors.lastname: Choi
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Notterman
authors.forename: Krista M D
authors.initials: KM
authors.lastname: La Perle
mesh_terms: 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
chemical_list: D015703:Antigens, CD; D054778:NM23 Nucleoside Diphosphate Kinases; D012333:RNA, Messenger; D005914:Globins; D007501:Iron