CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability
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 mic...
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| Veröffentlicht in: | The Journal of experimental medicine 2015-08, Vol.212 (9), p.1465-1479 |
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| creator | Inoue, Takeshi Morita, Masahiro Hijikata, Atsushi Fukuda-Yuzawa, Yoko Adachi, Shungo Isono, Kyoichi Ikawa, Tomokatsu Kawamoto, Hiroshi Koseki, Haruhiko Natsume, Tohru Fukao, Taro Ohara, Osamu Yamamoto, Tadashi Kurosaki, Tomohiro |
| description | 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. |
| doi_str_mv | 10.1084/jem.20150384 |
| format | Article |
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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.</description><identifier>ISSN: 0022-1007</identifier><identifier>EISSN: 1540-9538</identifier><identifier>DOI: 10.1084/jem.20150384</identifier><identifier>PMID: 26238124</identifier><language>eng</language><publisher>United States: The Rockefeller University Press</publisher><subject>Animals ; B-Lymphocytes - cytology ; B-Lymphocytes - immunology ; Cell Differentiation - genetics ; Cell Differentiation - immunology ; Gene Rearrangement, B-Lymphocyte, Heavy Chain - genetics ; Gene Rearrangement, B-Lymphocyte, Heavy Chain - immunology ; Mice ; Mice, Transgenic ; RNA Stability - genetics ; RNA Stability - immunology ; RNA, Messenger - genetics ; RNA, Messenger - immunology ; Transcription Factors - genetics ; Transcription Factors - immunology ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - immunology</subject><ispartof>The Journal of experimental medicine, 2015-08, Vol.212 (9), p.1465-1479</ispartof><rights>2015 Inoue et al.</rights><rights>2015 Inoue et al. 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c413t-ab1fb25b01c7d96b630ab837b0ab2c64ea7dda1515bb480b6fe5579023e4bd7b3</citedby><cites>FETCH-LOGICAL-c413t-ab1fb25b01c7d96b630ab837b0ab2c64ea7dda1515bb480b6fe5579023e4bd7b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26238124$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Inoue, Takeshi</creatorcontrib><creatorcontrib>Morita, Masahiro</creatorcontrib><creatorcontrib>Hijikata, Atsushi</creatorcontrib><creatorcontrib>Fukuda-Yuzawa, Yoko</creatorcontrib><creatorcontrib>Adachi, Shungo</creatorcontrib><creatorcontrib>Isono, Kyoichi</creatorcontrib><creatorcontrib>Ikawa, Tomokatsu</creatorcontrib><creatorcontrib>Kawamoto, Hiroshi</creatorcontrib><creatorcontrib>Koseki, Haruhiko</creatorcontrib><creatorcontrib>Natsume, Tohru</creatorcontrib><creatorcontrib>Fukao, Taro</creatorcontrib><creatorcontrib>Ohara, Osamu</creatorcontrib><creatorcontrib>Yamamoto, Tadashi</creatorcontrib><creatorcontrib>Kurosaki, Tomohiro</creatorcontrib><title>CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability</title><title>The Journal of experimental medicine</title><addtitle>J Exp Med</addtitle><description>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.</description><subject>Animals</subject><subject>B-Lymphocytes - cytology</subject><subject>B-Lymphocytes - immunology</subject><subject>Cell Differentiation - genetics</subject><subject>Cell Differentiation - immunology</subject><subject>Gene Rearrangement, B-Lymphocyte, Heavy Chain - genetics</subject><subject>Gene Rearrangement, B-Lymphocyte, Heavy Chain - immunology</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>RNA Stability - genetics</subject><subject>RNA Stability - immunology</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - immunology</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - immunology</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - immunology</subject><issn>0022-1007</issn><issn>1540-9538</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkT1LBDEQhoMoen501pLSwtXJ914j6OEXiIJoHZLduXMluzmTPeH-vaunop3VFPPw8M68hOwzOGZQypMXbI85MAWilGtkxJSEYqxEuU5GAJwXDMBske2cXwCYlEpvki2uuSgZlyOCk7v7R0Gr2PWp8YseM-0jRZfCkp7TCkOgNb5hiPMWu5765QqNITTdjN7Mnmka4OS6GX4CrqvpXAnaPtyd0dw734SmX-6SjakLGfe-5g55urx4nFwXt_dXN5Oz26KSTPSF82zqufLAKlOPtdcCnC-F8cPglZboTF07ppjyXpbg9RSVMmPgAqWvjRc75HTlnS98i3U1JEou2HlqWpeWNrrG_t10zbOdxTcr1eBTehAcfglSfF1g7m3b5I8vuA7jIltmGFfalIb9AwWjlJYAA3q0QqsUc044_UnEwH6UaIcS7XeJA37w-4of-Ls18Q7lWZjb</recordid><startdate>20150824</startdate><enddate>20150824</enddate><creator>Inoue, Takeshi</creator><creator>Morita, Masahiro</creator><creator>Hijikata, Atsushi</creator><creator>Fukuda-Yuzawa, Yoko</creator><creator>Adachi, Shungo</creator><creator>Isono, Kyoichi</creator><creator>Ikawa, Tomokatsu</creator><creator>Kawamoto, Hiroshi</creator><creator>Koseki, Haruhiko</creator><creator>Natsume, Tohru</creator><creator>Fukao, Taro</creator><creator>Ohara, Osamu</creator><creator>Yamamoto, Tadashi</creator><creator>Kurosaki, Tomohiro</creator><general>The Rockefeller University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7T5</scope><scope>7TO</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20150824</creationdate><title>CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability</title><author>Inoue, Takeshi ; 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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. 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| subjects | Animals B-Lymphocytes - cytology B-Lymphocytes - immunology Cell Differentiation - genetics Cell Differentiation - immunology Gene Rearrangement, B-Lymphocyte, Heavy Chain - genetics Gene Rearrangement, B-Lymphocyte, Heavy Chain - immunology Mice Mice, Transgenic RNA Stability - genetics RNA Stability - immunology RNA, Messenger - genetics RNA, Messenger - immunology Transcription Factors - genetics Transcription Factors - immunology Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - immunology |
| title | CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability |
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