Targeted Sos1 deletion reveals its critical role in early T-cell development

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-07, Vol.108 (30), p.12407-12412
• Main Authors: Kortum, Robert L, Sommers, Connie L, Alexander, Clayton P, Pinski, John M, Li, Wenmei, Grinberg, Alex, Lee, Jan, Love, Paul E, Samelson, Lawrence E
• Format: Article
• Language: English
• Subjects: alleles; Animals; Biological Sciences; Cell Differentiation - immunology; Cell Proliferation; Cellular receptors; Clonal selection; Data processing; Developmental biology; Developmental stages; Differentiation; Extracellular signal-regulated kinase; Female; Gene deletion; Gene expression; Gene Targeting; Glycoproteins; Guanine; guanine nucleotide exchange factor; Guanine Nucleotide Exchange Factors - immunology; Guanine nucleotide-binding protein; Lymphocytes; Lymphocytes T; Male; Mice; Mice, Knockout; mitogen-activated protein kinase; Models, Immunological; Negative selection; Phosphorylation; Positive selection; Ras protein; Receptors; Receptors, Antigen, T-Cell - metabolism; Rodents; Signal transduction; Signal Transduction - immunology; Son of Sevenless Proteins - immunology; SOS1 Protein - deficiency; SOS1 Protein - genetics; SOS1 Protein - immunology; T cell antigen receptors; T cell receptors; T lymphocytes; T-cell receptor; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Thymocytes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1104295108

Activation of the small G protein Ras is required for thymocyte differentiation. In thymocytes, Ras is activated by the Ras guanine exchange factors (RasGEFs) Sos1, Sos2, and RasGRP1. We report the development of a floxed allele of sos1 to assess the role of Sos1 during thymocyte development. Sos1 was required for pre–T-cell receptor (pre-TCR)– but not TCR-stimulated developmental signals. Sos1 deletion led to a partial block at the DN-to-DP transition. Sos1-deficient thymocytes showed reduced pre-TCR–stimulated proliferation, differentiation, and ERK phosphorylation. In contrast, TCR-stimulated positive selection, and negative selection under strong stimulatory conditions, remained intact in Sos1-deficient mice. Comparison of RasGEF expression at different developmental stages showed that relative to Sos2 and RasGRP1, Sos1 is most abundant in DN thymocytes, but least abundant in DP thymocytes. These data reveal that Sos1 is uniquely positioned to affect signal transduction early in thymocyte development.