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The combined absence of the transcription factors Rel and RelA leads to multiple hemopoietic cell defects

Grossmann, Mathis and Metcalf, Donald and Merryfull, Julie and Beg, Amer and Baltimore, David and Gerondakis, Steve (1999) The combined absence of the transcription factors Rel and RelA leads to multiple hemopoietic cell defects. Proceedings of the National Academy of Sciences of the United States of America, 96 (21). pp. 11848-11853. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:GROpnas99

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Abstract

Individual Rel/NF-kappa B transcription factors, although dispensable for the development and maturation of most hemopoietic cells, are critical regulators of normal immune function. Redundancy among these proteins prompted us to examine the role of Rel and RelA in hemopoiesis by using mice that lack both subunits. Because of the death of double-mutant fetuses at day 13.5 of gestation (E13.5), E12 fetal liver hemopoietic progenitors were used for in vitro cultures and for repopulating stem cell studies in lethally irradiated normal recipient mice. Most striking, Rel/RelA-deficient hemopoietic precursors failed to promote the survival of myeloablated mice. This phenotype was associated with several defects including a reduction of spleen colony-forming unit progenitors, impaired erythropoiesis, and a deregulated expansion of granulocytes. In vitro progenitor assays also revealed that Rel or RelA serves an antiapoptotic role during monocyte differentiation. Despite the combined loss of Rel and RelA leading to these hemopoietic defects, c-rel(-/-)rela(-/-) stem cells contributed to the development of all lineages in mice engrafted with double-mutant fetal liver cells and normal bone marrow cells, albeit in a reduced fashion compared with controls. Collectively, these data indicate the loss of Rel and RelA does not appear to affect pluripotent stem cells; rather, Rel and RelA serve redundant functions in regulating differentiation and survival of committed progenitors in multiple hemopoietic lineages.


Item Type:Article
Additional Information:© 1999 The National Academy of Sciences. Communicated by Gustav J. V. Nossal, University of Melbourne, Parkville, Australia, August 6, 1999 (received for review April 26, 1999). We thank Drs. Andreas Strasser and Andrew Elefanty for antibodies and technical advice, Dr. Frank Battye and colleagues for assistance with cell sorting, and Drs. Warren Alexander, Yukio Nakamura, and Andreas Strasser for critical discussions and comments on the manuscript. This work was supported by the National Health and Medical Research Council (Australia), the Anti-Cancer Council of Victoria, Commonwealth AIDS Research Grants (no. 971274), and the International Association for Cancer Research (St. Andrew, U.K.).
Subject Keywords:NF-KAPPA-B, MICE LACKING, EMBRYONIC LETHALITY, ACTIVATION, APOPTOSIS, ALPHA, MOUSE, GENE, PHOSPHORYLATION, PROTOONCOGENE
Record Number:CaltechAUTHORS:GROpnas99
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:GROpnas99
Alternative URL:http://www.pnas.org/cgi/content/abstract/96/21/11848
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:578
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:26 Aug 2005
Last Modified:26 Dec 2012 08:40

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