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Mol. Cell. Biol. doi:10.1128/MCB.01871-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Thymomegaly, Microsplenia and Defective Homeostatic Proliferation of Peripheral Lymphocytes in p51-Ets1 Isoform-Specific Null Mice

Hollings Cancer Center, College of Graduate Studies, Molecular and Cellular Biology and Pathobiology Program, Department of Medicine, Experimental Hematology, Hematology and Oncology, Department of Pathology and Laboratory Medicine, Department of Cell Biology and Anatomy, Medical University of South Carolina, 171 Ashley Avenue, Charleston South Carolina 29425

^* To whom correspondence should be addressed. Email: spyropdd{at}musc.edu.

	Abstract

Ets1 is a member of the Ets transcription factor family. Alternative splicing of exon VII results in two naturally occurring protein isoforms: full-length Ets1 (p51-Ets1) and Ets1^VII (p42-Ets1). These isoforms bear key distinctions regarding protein-protein interactions, DNA binding kinetics and transcriptional target specificity. Disruption of both Ets1 isoforms in mice results in loss of detectable NK and NKT cell activity and defects in B- and T-lymphocytes. We generated mice that express only the Ets1^VII isoform. Ets1^VII homozygous mice express no p51-Ets1 and elevated levels of the p42-Ets1 protein relative to wild type and display increased perinatal lethality, thymomegaly and peripheral lymphopenia. Proliferation was increased in both the thymus and spleen, while apoptosis was decreased in the thymus and increased in the spleen of homozygotes. Significant elevations were observed in CD8⁺ and CD8⁺CD4⁺ thymocytes. Lymphoid cell (CD19⁺, CD4⁺, and CD8⁺) reductions predominantly contributed to diminished spleen cellularity, with fewer memory cells and a failure of homeostatic proliferation to maintain peripheral lymphocytes. Collectively, the Ets1^VII mutants demonstrate lymphocyte maturation defects associated with misregulation of p16^Ink4a, p27^Kip1 and CD44. Thus, a balance in the differential regulation of Ets1 isoforms represents a potential mechanism in the control of lymphoid maturation and homeostasis.