title: RasGRP1 and RasGRP3 Are Required for Efficient Generation of Early Thymic Progenitors.
abstract: T cell development is dependent on the migration of progenitor cells from the bone marrow to the thymus. Upon reaching the thymus, progenitors undergo a complex developmental program that requires inputs from various highly conserved signaling pathways including the Notch and Wnt pathways. To date, Ras signaling has not been implicated in the very earliest stages of T cell differentiation, but members of a family of Ras activators called RasGRPs have been shown to be involved at multiple stages of T cell development. We examined early T cell development in mice lacking RasGRP1, RasGRP3, and RasGRPs 1 and 3. We report that RasGRP1- and RasGRP3-deficient thymi show significantly reduced numbers of early thymic progenitors (ETPs) relative to wild type thymi. Furthermore, RasGRP1/3 double-deficient thymi show significant reductions in ETP numbers compared with either RasGRP1 or RasGRP3 single-deficient thymi, suggesting that both RasGRP1 and RasGRP3 regulate the generation of ETPs. In addition, competitive bone marrow chimera experiments reveal that RasGRP1/3 double-deficient progenitors intrinsically generate ETPs less efficiently than wild type progenitors. Finally, RasGRP1/3-deficient progenitors show impaired migration toward the CCR9 ligand, CCL25, suggesting that RasGRP1 and RasGRP3 may regulate progenitor entry into the thymus through a CCR9-dependent mechanism. These data demonstrate that, in addition to Notch and Wnt, the highly conserved Ras pathway is critical for the earliest stages of T cell development and further highlight the importance of Ras signaling during thymocyte maturation.
authors.affiliation: Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Golec
authors.affiliation: Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Henao Caviedes
authors.affiliation: Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada tbaldwin@ualberta.ca.
authors.forename: Troy A
authors.initials: TA
authors.lastname: Baldwin
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D019742:Chemokines, CC / Q000276:immunology; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D054503:Lymphoid Progenitor Cells / Q000276:immunology / Q000502:physiology; D051379:Mice; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology / Q000502:physiology; D054388:Receptors, CCR / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D060168:Thymocytes / Q000276:immunology / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D020663:ras Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C119309:CC chemokine receptor 9; C491541:Ccl25 protein, mouse; D019742:Chemokines, CC; D020662:Guanine Nucleotide Exchange Factors; C526545:RasGRP3 protein, mouse; C112278:Rasgrp1 protein, mouse; C485927:Rasgrp2 protein, mouse; D054388:Receptors, CCR; D020663:ras Guanine Nucleotide Exchange Factors