Early Growth Response Transcription Factors Are Required for Development of CD4^-CD8^- Thymocytes to the CD4⁺CD8⁺ Stage¹
Journal of Immunology, 2002, 168: 1649-1658.

(Note: Current Rosetta Inpharmatics employees are shown in boldface type.)

Michael Carleton^2,*, Mariëlle C. Haks^2,*,†, Sigrid A. A. Smeele^†, Allan Jones‡, Stanley M. Belkowski^*, Marc A. Berger^4,*, Peter Linsley^‡, Ada M. Kruisbeek^‡ and David L. Wiest^3,*

Abstract

Progression of immature CD4-CD8- thymocytes beyond the -selection checkpoint to the CD4+CD8+ stage requires activation of the pre-TCR complex; however, few of the DNA-binding proteins that serve as molecular effectors of those pre-TCR signals have been identified. We demonstrate in this study that members of the early growth response (Egr) family of transcription factors are critical effectors of the signals that promote this developmental transition. Specifically, the induction of three Egr family members (Egr1, 2, and 3) correlates with pre-TCR activation and development of CD4-CD8- thymocytes beyond the -selection checkpoint. Enforced expression of each of these Egr factors is able to bypass the block in thymocyte development associated with defective pre-TCR function. However, Egr family members may play somewhat distinct roles in promoting thymocyte development, because there are differences in the genes modulated by enforced expression of particular Egr factors. Finally, interfering with Egr function using dominant-negative proteins disrupts thymocyte development from the CD4-CD8- to the CD4+CD8+ stage. Taken together, these data demonstrate that the Egr proteins play an essential role in executing the differentiation program initiated by pre-TCR signaling.

^* Immunobiology Working Group, Division of Basic Sciences, Fox Chase Cancer Center, Philadelphia, PA 19111; ^† Division of Immunology, The Netherlands Cancer Institute, Amersterdam, The Netherlands; and ^‡ Rosetta Inpharmatics, Kirkland, WA 98034

2 M.C. and M.C.H. contributed equally to this work.
3 Address correspondence and reprint requests to: Dr. David L. Wiest, Fox Chase Cancer Center, Division of Basic Sciences, Immunobiology Working Group, 7701 Burholme Avenue, Philadelphia, PA 19111. E-mail address: DL_Wiest@FCCC.edu
4 Current address: Purdue BioPharma, Princeton, NJ 08540.