title: Phosphatase Wip1 controls antigen-independent B-cell development in a p53-dependent manner.
abstract: Wild-type p53-induced phosphatase 1 (Wip1), a phosphatase previously considered as an oncogene, has been implicated in the regulation of thymus homeostasis and neutrophil maturation. However, the role of Wip1 in B-cell development is unknown. We show that Wip1-deficient mice exhibit a significant reduction of B-cell numbers in the bone marrow, peripheral blood, and spleen. A reciprocal transplantation approach revealed a cell-intrinsic defect in early B-cell precursors caused by Wip1 deficiency. Further experiments revealed that Wip1 deficiency led to a sustained activation of p53 in B cells, which led to increased level of apoptosis in the pre-B-cell compartment. Notably, the impairment of B-cell development in Wip1-deficient mice was completely rescued by genetic ablation of p53, but not p21. Therefore, loss of Wip1 phosphatase induces a p53-dependent, but p21-independent, mechanism that impairs B-cell development by enhancing apoptosis in early B-cell precursors. Moreover, Wip1 deficiency exacerbated a decline in B-cell development caused by aging as evidenced in mice with aging and mouse models with serial competitive bone marrow transplantation, respectively. Our present data indicate that Wip1 plays a critical role in maintaining antigen-independent B-cell development in the bone marrow and preventing an aging-related decline in B-cell development.
authors.affiliation: Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou, China;
authors.forename: Weiwei
authors.initials: W
authors.lastname: Yi
authors.affiliation: Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China;
authors.forename: Xuelian
authors.initials: X
authors.lastname: Hu
authors.affiliation: Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou, China; Leibniz Institute for Age Research-Fritz Lipmann Institute, Jena, Germany;
authors.forename: Zhiyang
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou, China; Sir Runrun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China;
authors.forename: Leiming
authors.initials: L
authors.lastname: Liu
authors.affiliation: Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China;
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China;
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou, China;
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Cong
authors.affiliation: Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China;
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health; Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; and.
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Leibniz Institute for Age Research-Fritz Lipmann Institute, Jena, Germany;
authors.forename: Karl Lenhard
authors.initials: KL
authors.lastname: Rudolph
authors.affiliation: Department of Pediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Ministry of Education Key Laboratory of Birth Defects, Sichuan University, Chengdu, China.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China;
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou, China;
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ju
mesh_terms: D000375:Aging / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005260:Female; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010749:Phosphoprotein Phosphatases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C