title: The catalytic activity of the mitogen-activated protein kinase extracellular signal-regulated kinase 3 is required to sustain CD4+ CD8+ thymocyte survival.
abstract: Extracellular signal-regulated kinase 3 (ERK3) is an atypical member of the mitogen-activated protein kinase (MAPK) family whose function is largely unknown. Given the central role of MAPKs in T cell development, we hypothesized that ERK3 may regulate thymocyte development. Here we have shown that ERK3 deficiency leads to a 50% reduction in CD4(+) CD8(+) (DP) thymocyte number. Analysis of hematopoietic chimeras revealed that the reduction in DP thymocytes is intrinsic to hematopoietic cells. We found that early thymic progenitors seed the Erk3(-/-) thymus and can properly differentiate and proliferate to generate DP thymocytes. However, ERK3 deficiency results in a decrease in the DP thymocyte half-life, associated with a higher level of apoptosis. As a consequence, ERK3-deficient DP thymocytes are impaired in their ability to make successful secondary T cell receptor alpha (TCRα) gene rearrangement. Introduction of an already rearranged TCR transgene restores thymic cell number. We further show that knock-in of a catalytically inactive allele of Erk3 fails to rescue the loss of DP thymocytes. Our results uncover a unique role for ERK3, dependent on its kinase activity, during T cell development and show that this atypical MAPK is essential to sustain DP survival during RAG-mediated rearrangements.
authors.affiliation: Maisonneuve-Rosemont Hospital Research Centre, Montreal, Quebec, Canada Department of Microbiology, Infectiology and Immunology, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Miriam
authors.initials: M
authors.lastname: Marquis
authors.affiliation: Maisonneuve-Rosemont Hospital Research Centre, Montreal, Quebec, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Daudelin
authors.affiliation: Maisonneuve-Rosemont Hospital Research Centre, Montreal, Quebec, Canada.
authors.forename: Salix
authors.initials: S
authors.lastname: Boulet
authors.affiliation: Maisonneuve-Rosemont Hospital Research Centre, Montreal, Quebec, Canada Department of Microbiology, Infectiology and Immunology, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Julien
authors.initials: J
authors.lastname: Sirois
authors.affiliation: Maisonneuve-Rosemont Hospital Research Centre, Montreal, Quebec, Canada.
authors.forename: Karinn
authors.initials: K
authors.lastname: Crain
authors.affiliation: Program in Molecular Biology, University of Montreal, Montreal, Quebec, Canada Institute of Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Mathien
authors.affiliation: Program in Molecular Biology, University of Montreal, Montreal, Quebec, Canada Institute of Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Turgeon
authors.affiliation: Program in Molecular Biology, University of Montreal, Montreal, Quebec, Canada Institute of Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Justine
authors.initials: J
authors.lastname: Rousseau
authors.affiliation: Department of Pharmacology, University of Montreal, Montreal, Quebec, Canada Program in Molecular Biology, University of Montreal, Montreal, Quebec, Canada nathalie.labrecque@umontreal.ca sylvain.meloche@umontreal.ca.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Meloche
authors.affiliation: Maisonneuve-Rosemont Hospital Research Centre, Montreal, Quebec, Canada Department of Microbiology, Infectiology and Immunology, University of Montreal, Montreal, Quebec, Canada Department of Medicine, University of Montreal, Montreal, Quebec, Canada nathalie.labrecque@umontreal.ca sylvain.meloche@umontreal.ca.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Labrecque
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D020134:Catalytic Domain; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival; D004622:Embryo, Mammalian; D055879:Gene Knock-In Techniques; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048053:Mitogen-Activated Protein Kinase 6 / Q000235:genetics* / Q000378:metabolism*; D060168:Thymocytes / Q000166:cytology* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology*
chemical_list: C474633:Mapk6 protein, mouse; D048053:Mitogen-Activated Protein Kinase 6