title: E2F-2 Promotes Nuclear Condensation and Enucleation of Terminally Differentiated Erythroblasts.
abstract: E2F-2 is a retinoblastoma (Rb)-regulated transcription factor induced during terminal erythroid maturation. Cyclin E-mediated Rb hyperphosphorylation induces E2F transcriptional activator functions. We previously reported that deregulated cyclin E activity causes defective terminal maturation of nucleated erythroblasts in vivo Here, we found that these defects are normalized by E2F-2 deletion; however, anemia in mice with deregulated cyclin E is not improved by E2F-2-loss, which itself causes reduced peripheral red blood cell (RBC) counts without altering relative abundances of erythroblast subpopulations. To determine how E2F-2 regulates RBC production, we comprehensively studied erythropoiesis using knockout mice and hematopoietic progenitors. We found that efficient stress erythropoiesis in vivo requires E2F-2, and we also identified an unappreciated role for E2F-2 in erythroblast enucleation. In particular, E2F-2 deletion impairs nuclear condensation, a morphological feature of maturing erythroblasts. Transcriptome profiling of E2F-2-null, mature erythroblasts demonstrated widespread changes in gene expression. Notably, we identified citron Rho-interacting kinase (CRIK), which has known functions in mitosis and cytokinesis, as induced in erythroblasts in an E2F-2-dependent manner, and we found that CRIK activity promotes efficient erythroblast enucleation and nuclear condensation. Together, our data reveal novel, lineage-specific functions for E2F-2 and suggest that some mitotic kinases have specialized roles supporting enucleation of maturing erythroblasts.
authors: Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.|Driskill Graduate Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors: Kelsey L
authors: KL
authors: Swartz
authors: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin, USA.
authors: Scott N
authors: SN
authors: Wood
authors: Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.|Driskill Graduate Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors: Tushar
authors: T
authors: Murthy
authors: Section of Hematology, Yale Cancer Center, New Haven, Connecticut, USA.
authors: Oscar
authors: O
authors: Ramirez
authors: Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors: Gangjian
authors: G
authors: Qin
authors: Section of Hematology, Yale Cancer Center, New Haven, Connecticut, USA.
authors: Manoj M
authors: MM
authors: Pillai
authors: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin, USA.|Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.|Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors: Sridhar
authors: S
authors: Rao
authors: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin, USA alex.minella@bcw.edu.|Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.|Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors: Alex C
authors: http://orcid.org/0000-0001-6693-3362
authors: AC
authors: Minella
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism*; D019927:Cyclin E / Q000378:metabolism; D050703:E2F2 Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D004900:Erythroblasts / Q000166:cytology* / Q000378:metabolism; D004920:Erythropoiesis; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D016160:Retinoblastoma Protein / Q000378:metabolism
chemical_list: D019927:Cyclin E; D050703:E2F2 Transcription Factor; C493761:E2F2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D016160:Retinoblastoma Protein; C115635:citron-kinase; D017346:Protein Serine-Threonine Kinases
keywords: E2F; cell cycle; cell differentiation; enucleation; erythropoiesis; gene regulation; mouse models