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Molecular and Cellular Biology, May 2007, p. 3353-3366, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.01871-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

Tsukasa Higuchi,1,{dagger},{ddagger} Frank O. Bartel,1,2,{dagger} Masahiro Masuya,3,§ Takao Deguchi,3 Kelly W. Henderson,1,4 Runzhao Li,1,5 Robin C. Muise-Helmericks,1,6 Michael J. Kern,6 Dennis K. Watson,1,5 and Demetri D. Spyropoulos1,5*

Hollings Cancer Center,1 College of Graduate Studies, Molecular and Cellular Biology and Pathobiology Program,2 Department of Medicine, Experimental Hematology,3 Hematology and Oncology,4 Department of Pathology and Laboratory Medicine,5 Department of Cell Biology and Anatomy, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina 294256

Received 3 October 2006/ Returned for modification 18 December 2006/ Accepted 21 February 2007

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{Delta}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 the loss of detectable NK and NKT cell activity and defects in B and T lymphocytes. We generated mice that express only the Ets1{Delta}VII isoform. Ets1{Delta}VII homozygous mice express no p51-Ets1 and elevated levels of the p42-Ets1 protein relative to the wild type and display increased perinatal lethality, thymomegaly, and peripheral lymphopenia. Proliferation was increased in both the thymus and the spleen, while apoptosis was decreased in the thymus and increased in the spleen of homozygotes. Significant elevations of CD8+ and CD8+CD4+ thymocytes were observed. Lymphoid cell (CD19+, CD4+, and CD8+) reductions were predominantly responsible for diminished spleen cellularity, with fewer memory cells and a failure of homeostatic proliferation to maintain peripheral lymphocytes. Collectively, the Ets1{Delta}VII mutants demonstrate lymphocyte maturation defects associated with misregulation of p16Ink4a, p27Kip1, and CD44. Thus, a balance in the differential regulation of Ets1 isoforms represents a potential mechanism in the control of lymphoid maturation and homeostasis.

* Corresponding author. Mailing address: Hollings Cancer Center, Room 317, 86 Jonathan Lucas St., Charleston, SC 29425. Phone: (843) 792-7049. Fax: (843) 792-5002. E-mail: spyropdd{at}musc.edu

{triangledown} Published ahead of print on 5 March 2007.

{dagger} T.H. and F.O.B. contributed equally to this work.

{ddagger} Present address: First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, 3-1-1 Asahi, Matsumoto 390-8621, Japan.

§ Present address: Division of Blood Transfusion, Mie University Hospital, Takao Deguchi, Department of Pediatrics, Mie University School of Medicine, 2-174 Edobashi, Tsu City, Mie 514-8507, Japan.

Molecular and Cellular Biology, May 2007, p. 3353-3366, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.01871-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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