title: CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability.
abstract: The CCR4-NOT deadenylase complex plays crucial roles in mRNA decay and translational repression induced by poly(A) tail shortening. Although the in vitro activities of each component of this complex have been well characterized, its in vivo role in immune cells remains unclear. Here we show that mice lacking the CNOT3 subunit of this complex, specifically in B cells, have a developmental block at the pro- to pre-B cell transition. CNOT3 regulated generation of germline transcripts in the VH region of the immunoglobulin heavy chain (Igh) locus, compaction of the locus, and subsequent Igh gene rearrangement and destabilized tumor suppressor p53 mRNA. The developmental defect in the absence of CNOT3 could be partially rescued by ablation of p53 or introduction of a pre-rearranged Igh transgene. Thus, our data suggest that the CCR4-NOT complex regulates B cell differentiation by controlling Igh rearrangement and destabilizing p53 mRNA.
authors.affiliation: Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Biochemistry and Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada Department of Biochemistry and Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Morita
authors.affiliation: Laboratory for Integrative Genomics, Laboratory for Developmental Genetics, Laboratory for Immune Regeneration, and Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hijikata
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Fukuda-Yuzawa
authors.affiliation: Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), Koto-ku, Tokyo 135-0064, Japan.
authors.forename: Shungo
authors.initials: S
authors.lastname: Adachi
authors.affiliation: Laboratory for Integrative Genomics, Laboratory for Developmental Genetics, Laboratory for Immune Regeneration, and Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Isono
authors.affiliation: Laboratory for Integrative Genomics, Laboratory for Developmental Genetics, Laboratory for Immune Regeneration, and Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa 230-0045, Japan Laboratory for Lymphocyte Development, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Tomokatsu
authors.initials: T
authors.lastname: Ikawa
authors.affiliation: Laboratory for Lymphocyte Development, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan Department of Immunology, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawamoto
authors.affiliation: Laboratory for Integrative Genomics, Laboratory for Developmental Genetics, Laboratory for Immune Regeneration, and Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.affiliation: Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), Koto-ku, Tokyo 135-0064, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Natsume
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
authors.forename: Taro
authors.initials: T
authors.lastname: Fukao
authors.affiliation: Laboratory for Integrative Genomics, Laboratory for Developmental Genetics, Laboratory for Immune Regeneration, and Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.affiliation: Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Onna, Okinawa 904-0495, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan Laboratory for Integrative Genomics, Laboratory for Developmental Genetics, Laboratory for Immune Regeneration, and Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa 230-0045, Japan kurosaki@ifrec.osaka-u.ac.jp.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kurosaki
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D020871:RNA Stability / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology*
chemical_list: C569362:CNOT3 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53