Interplay between RORgammat, Egr3, and E proteins controls proliferation in response to pre-TCR signals.
The response of thymocytes to pre-T cell receptor (pre-TCR) signaling includes proliferation and gene rearrangement, two cellular processes that are incompatible. The control of proliferation by pre-TCR signals depends on the activities of the transcription factors RORgammat, Egr3, E12, and E47. Here, we describe a regulatory network in which interplay between these factors ensures transient proliferation that is temporally distinct from gene rearrangement. RORgammat expression was elevated after pre-TCR signaling, and RORgammat promoted gene rearrangement in CD4+, CD8+ cells by inhibiting cell division, promoting survival via Bcl-X(L), and inducing Rag2. Egr3 was transiently induced by pre-TCR signals and promoted a distinct proliferative phase by reducing E protein-dependent RORgammat expression and interacting with RORgammat to prevent induction of target genes. After Egr3 subsided, the expression and function of RORgammat increased. Thus, transient induction of Egr3 delays the effects of RORgammat and enables pre-TCR signaling to induce both proliferation and gene rearrangement.
Xi
Hongkang
H
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 101 Woodruff Circle, Atlanta, Georgia 30322.
Schwartz
Ruth
R
Division of Biological Sciences, University of California, San Diego, La Jolla, California 92903.
Engel
Isaac
I
La Jolla Institute for Allergy and Immunology, San Diego, California 92121.
Murre
Cornelis
C
Division of Biological Sciences, University of California, San Diego, La Jolla, California 92903.
Kersh
Gilbert J
GJ
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 101 Woodruff Circle, Atlanta, Georgia 30322. Electronic address: gkersh@emory.edu.
D000818:Animals; D024721:E-Box Elements; D051776:Early Growth Response Protein 3 / Q000235:genetics / Q000378:metabolism*; D015329:Gene Rearrangement, T-Lymphocyte; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins / Q000235:genetics; D051381:Rats; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D051820:TCF Transcription Factors / Q000378:metabolism*; D058125:Transcription Factor 7-Like 1 Protein
C477604:Cpeb4 protein, mouse; D051796:Inhibitor of Differentiation Proteins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D016601:RNA-Binding Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C539901:Rorc protein, mouse; C539902:Rorc protein, rat; D051820:TCF Transcription Factors; C544913:Tcf7l1 protein, mouse; C553060:Tcf7l1 protein, rat; D058125:Transcription Factor 7-Like 1 Protein; C067679:Idb3 protein, mouse; D051776:Early Growth Response Protein 3