title: Cyclin A2 regulates erythrocyte morphology and numbers.
abstract: Cyclin A2 is an essential gene for development and in haematopoietic stem cells and therefore its functions in definitive erythropoiesis have not been investigated. We have ablated cyclin A2 in committed erythroid progenitors in vivo using erythropoietin receptor promoter-driven Cre, which revealed its critical role in regulating erythrocyte morphology and numbers. Erythroid-specific cyclin A2 knockout mice are viable but displayed increased mean erythrocyte volume and reduced erythrocyte counts, as well as increased frequency of erythrocytes containing Howell-Jolly bodies. Erythroblasts lacking cyclin A2 displayed defective enucleation, resulting in reduced production of enucleated erythrocytes and increased frequencies of erythrocytes containing nuclear remnants. Deletion of the Cdk inhibitor p27Kip1but not Cdk2, ameliorated the erythroid defects resulting from deficiency of cyclin A2, confirming the critical role of cyclin A2/Cdk activity in erythroid development. Loss of cyclin A2 in bone marrow cells in semisolid culture prevented the formation of BFU-E but not CFU-E colonies, uncovering its essential role in BFU-E function. Our data unveils the critical functions of cyclin A2 in regulating mammalian erythropoiesis.
authors.affiliation: a Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research) , Singapore , Republic of Singapore.
authors.forename: Senthil Raja
authors.initials: SR
authors.lastname: Jayapal
authors.affiliation: b Genome Institute of Singapore , Singapore.
authors.forename: Heather Yin-Kuan
authors.initials: HY
authors.lastname: Ang
authors.affiliation: a Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research) , Singapore , Republic of Singapore.|c Cancer Science Institute of Singapore, National University of Singapore , Singapore.
authors.forename: Chelsia Qiuxia
authors.initials: CQ
authors.lastname: Wang
authors.affiliation: a Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research) , Singapore , Republic of Singapore.
authors.forename: Xavier
authors.initials: X
authors.lastname: Bisteau
authors.affiliation: a Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research) , Singapore , Republic of Singapore.|d National University of Singapore (NUS) , Department of Biochemistry , Singapore.
authors.forename: Matias J
authors.initials: MJ
authors.lastname: Caldez
authors.affiliation: a Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research) , Singapore , Republic of Singapore.
authors.forename: Gan Xiao
authors.initials: GX
authors.lastname: Xuan
authors.affiliation: a Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research) , Singapore , Republic of Singapore.
authors.forename: Weimiao
authors.initials: W
authors.lastname: Yu
authors.affiliation: a Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research) , Singapore , Republic of Singapore.
authors.forename: Vinay
authors.initials: V
authors.lastname: Tergaonkar
authors.affiliation: c Cancer Science Institute of Singapore, National University of Singapore , Singapore.
authors.forename: Motomi
authors.initials: M
authors.lastname: Osato
authors.affiliation: b Genome Institute of Singapore , Singapore.
authors.forename: Bing
authors.initials: B
authors.lastname: Lim
authors.affiliation: a Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research) , Singapore , Republic of Singapore.|d National University of Singapore (NUS) , Department of Biochemistry , Singapore.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kaldis
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism; D048430:Cell Shape; D002478:Cells, Cultured; D056751:Cyclin A2 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004249:DNA Damage; D004912:Erythrocytes / Q000166:cytology* / Q000378:metabolism*; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis; D049452:Green Fluorescent Proteins / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism
chemical_list: D056751:Cyclin A2; D017467:Receptors, Erythropoietin; D049452:Green Fluorescent Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C045073:Cre recombinase; D019426:Integrases; D001973:Bromodeoxyuridine
keywords: Animal models; BFU-E colonies; CFU-E colonies; Cyclin A2; Cyclins; DNA damage and repair; G1/S transition; Hematopoiesis; Howell-Jolly bodies; Protein kinases; Stem cells; enucleation; erythropoiesis