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Redundant Role for Early Growth Response Transcriptional Regulators in Thymocyte Differentiation and Survival¹

John H. Carter^*, Juliet M. Lefebvre, David L. Wiest and Warren G. Tourtellotte^2,*,,

^* Department of Pathology, Division of Neuropathology, and Department of Neurology, Northwestern University, Chicago IL, 60611; and Immunobiology Working Group, Division of Basic Sciences, Fox Chase Cancer Center, Philadelphia, PA 19111

The early growth response (Egr) family of transcriptional regulators consists of four proteins that share highly conserved DNA-binding domains. In many cell types, they are coexpressed and appear to have cooperative roles in regulating gene expression during growth and differentiation. Three Egr proteins, Egr1, Egr2, and Egr3, are induced during thymocyte differentiation in response to pre-TCR signaling, suggesting they may be critical for some aspects of pre-TCR-mediated differentiation. Indeed, enforced expression of Egr proteins in developing thymocytes can recapitulate some aspects of pre-TCR signaling, but the mechanisms by which they contribute to -selection are still poorly understood. Egr3 stimulates proliferation of -selected thymocytes, and Egr3-deficient mice have hypocellular thymuses, defects in proliferation, and impaired progression from double-negative 3 to double-negative 4. Surprisingly, Egr1-deficient mice exhibit normal -selection, indicating that the functions of Egr1 during -selection are likely compensated by other Egr proteins. In this study, we show that mice lacking both Egr1 and Egr3 exhibit a more severe thymic atrophy and impairment of thymocyte differentiation than mice lacking either Egr1 or Egr3. This is due to a proliferation defect and cell-autonomous increase in apoptosis, indicating that Egr1 and Egr3 cooperate to promote thymocyte survival. Microarray analysis of deregulated gene expression in immature thymocytes lacking both Egr1 and Egr3 revealed a previously unknown role for Egr proteins in the maintenance of cellular metabolism, providing new insight into the function of these molecules during T cell development.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health (NS046468 and NS040748) and a Howard Hughes Faculty Scholar Award (to W.G.T.). J.H.C. was supported by a Predoctoral Fellowship from the National Institutes of Health (CA009560) and the National Institutes of Health Medical Scientist Training Program (GM008152).

² Address correspondence and reprint requests to Dr. Warren G. Tourtellotte, Department of Pathology, Northwestern University, W127, 330 East Chicago Avenue, Chicago, IL 60611. E-mail address: warren{at}northwestern.edu

³ Abbreviations used in this paper: DN, double negative; DP, double positive; SP, single positive; pT, pre-TCR; Egr, early growth response; 1/3 DKO, Egr1 and Egr3 double knockout; WT, wild type; 7-AAD, 7-aminoactinomycin D; qPCR, quantitative real-time PCR; P, postnatal day; GO, Gene Ontology; TFBS, transcription factor-binding site; HSC, hemopoietic stem cell.

⁴ The online version of this article contains supplemental material.

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