title: MYSM1-dependent checkpoints in B cell lineage differentiation and B cell-mediated immune response.
abstract: MYSM1 is a chromatin-binding histone deubiquitinase.MYSM1mutations in humans result in lymphopenia whereas loss ofMysm1in mice causes severe hematopoietic abnormalities, including an early arrest in B cell development. However, it remains unknown whether MYSM1 is required at later checkpoints in B cell development or for B cell-mediated immune responses. We analyzed conditional mouse modelsMysm1fl/flTg.mb1-cre,Mysm1fl/flTg.CD19-cre, andMysm1fl/flTg.CD21-cre with inactivation ofMysm1at prepro-B, pre-B, and follicular B cell stages of development. We show that loss ofMysm1at the prepro-B cell stage inMysm1fl/flTg.mb1-cre mice results in impaired B cell differentiation, with an ∼2-fold reduction in B cell numbers in the lymphoid organs.Mysm1fl/flTg.mb1-cre B cells also showed increased expression of activation markers and impaired survival and proliferation. In contrast,Mysm1was largely dispensable from the pre-B cell stage onward, withMysm1fl/flTg.CD19-cre andMysm1fl/flTg.CD21-cre mice showing no alterations in B cell numbers and largely normal responses to stimulation. MYSM1, therefore, has an essential role in B cell lineage specification but is dispensable at later stages of development. Importantly, MYSM1 activity at the prepro-B cell stage of development is important for the normal programming of B cell responses to stimulation once they complete their maturation process.
authors.affiliation: Department of Physiology, McGill University, Montreal, Quebec, Canada.|McGill University Research Centre on Complex Traits, Montreal, Quebec, Canada; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Förster
authors.affiliation: Department of Physiology, McGill University, Montreal, Quebec, Canada.|McGill University Research Centre on Complex Traits, Montreal, Quebec, Canada; and.
authors.forename: Kyo
authors.initials: K
authors.lastname: Farrington
authors.affiliation: Department of Physiology, McGill University, Montreal, Quebec, Canada.|McGill University Research Centre on Complex Traits, Montreal, Quebec, Canada; and.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Petrov
authors.affiliation: Department of Physiology, McGill University, Montreal, Quebec, Canada.|McGill University Research Centre on Complex Traits, Montreal, Quebec, Canada; and.
authors.forename: Jad I
authors.initials: JI
authors.lastname: Belle
authors.affiliation: McGill University Research Centre on Complex Traits, Montreal, Quebec, Canada; and.|Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Mindt
authors.affiliation: Department of Physiology, McGill University, Montreal, Quebec, Canada.|McGill University Research Centre on Complex Traits, Montreal, Quebec, Canada; and.
authors.forename: Mariko
authors.initials: M
authors.lastname: Witalis
authors.affiliation: McGill University Research Centre on Complex Traits, Montreal, Quebec, Canada; and.|Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
authors.forename: Claudia U
authors.initials: CU
authors.lastname: Duerr
authors.affiliation: McGill University Research Centre on Complex Traits, Montreal, Quebec, Canada; and.|Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
authors.forename: Jörg H
authors.initials: JH
authors.lastname: Fritz
authors.affiliation: Department of Physiology, McGill University, Montreal, Quebec, Canada; anastasia.nijnik@mcgill.ca.|McGill University Research Centre on Complex Traits, Montreal, Quebec, Canada; and.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Nijnik
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D015415:Biomarkers / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage; D049109:Cell Proliferation; D002470:Cell Survival; D010450:Endopeptidases / Q000378:metabolism*; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D017578:Immunoglobulin Class Switching; D019426:Integrases / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017464:Receptors, Complement 3d / Q000378:metabolism; D015534:Trans-Activators; D064570:Ubiquitin-Specific Proteases
chemical_list: D015415:Biomarkers; D017464:Receptors, Complement 3d; D015534:Trans-Activators; C045073:Cre recombinase; D019426:Integrases; D010450:Endopeptidases; C570173:MYSM1 protein, mouse; D064570:Ubiquitin-Specific Proteases
keywords: B cell development; conditional knockout mice; humoral immunity