T396I mutation of mouse Sufu reduces the stability and activity of Gli3 repressor
Hedgehog signaling is primarily transduced by two transcription factors: Gli2, which mainly acts as a full-length activator, and Gli3, which tends to be proteolytically processed from a full-length form (Gli3FL) to an N-terminal repressor (Gli3REP). Recent studies using a Sufu knockout mouse have in...
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| creator | Makino, Shigeru Zhulyn, Olena Mo, Rong Puviindran, Vijitha Zhang, Xiaoyun Murata, Takuya Fukumura, Ryutaro Ishitsuka, Yuichi Kotaki, Hayato Matsumaru, Daisuke Ishii, Shunsuke Hui, Chi-Chung Gondo, Yoichi |
| description | Hedgehog signaling is primarily transduced by two transcription factors: Gli2, which mainly acts as a full-length activator, and Gli3, which tends to be proteolytically processed from a full-length form (Gli3FL) to an N-terminal repressor (Gli3REP). Recent studies using a Sufu knockout mouse have indicated that Sufu is involved in regulating Gli2 and Gli3 activator and repressor activity at multiple steps of the signaling cascade; however, the mechanism of specific Gli2 and Gli3 regulation remains to be elucidated. In this study, we established an allelic series of ENU-induced mouse strains. Analysis of one of the missense alleles, SufuT396I, showed that Thr396 residue of Sufu played a key role in regulation of Gli3 activity. SufuT396I/T396I embryos exhibited severe polydactyly, which is indicative of compromised Gli3 activity. Concomitantly, significant quantitative reductions of unprocessed Gli3 (Gli3FL) and processed Gli3 (Gli3REP) were observed in vivo as well as in vitro. Genetic experiments showed that patterning defects in the limb buds of SufuT396I/T396I were rescued by a constitutive Gli3REP allele (Gli3∆699), strongly suggesting that SufuT396I reduced the truncated Gli3 repressor. In contrast, SufuT396I qualitatively exhibited no mutational effects on Gli2 regulation. Taken together, the results of this study show that the Thr396 residue of Sufu is specifically required for regulation of Gli3 but not Gli2. This implies a novel Sufu-mediated mechanism in which Gli2 activator and Gli3 repressor are differentially regulated. |
| doi_str_mv | 10.1371/journal.pone.0119455 |
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Recent studies using a Sufu knockout mouse have indicated that Sufu is involved in regulating Gli2 and Gli3 activator and repressor activity at multiple steps of the signaling cascade; however, the mechanism of specific Gli2 and Gli3 regulation remains to be elucidated. In this study, we established an allelic series of ENU-induced mouse strains. Analysis of one of the missense alleles, SufuT396I, showed that Thr396 residue of Sufu played a key role in regulation of Gli3 activity. SufuT396I/T396I embryos exhibited severe polydactyly, which is indicative of compromised Gli3 activity. Concomitantly, significant quantitative reductions of unprocessed Gli3 (Gli3FL) and processed Gli3 (Gli3REP) were observed in vivo as well as in vitro. Genetic experiments showed that patterning defects in the limb buds of SufuT396I/T396I were rescued by a constitutive Gli3REP allele (Gli3∆699), strongly suggesting that SufuT396I reduced the truncated Gli3 repressor. In contrast, SufuT396I qualitatively exhibited no mutational effects on Gli2 regulation. Taken together, the results of this study show that the Thr396 residue of Sufu is specifically required for regulation of Gli3 but not Gli2. This implies a novel Sufu-mediated mechanism in which Gli2 activator and Gli3 repressor are differentially regulated.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0119455</identifier><identifier>PMID: 25760946</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alleles ; Animals ; Biology ; Body Patterning ; Cellular signal transduction ; Defects ; Drosophila ; Embryos ; Ethyl nitrosourea ; Extremities - growth & development ; Gene mutation ; Genetic aspects ; Genetics ; Genomes ; Genomics ; Hedgehog protein ; Hospitals ; Insects ; Isoleucine - metabolism ; Kinases ; Kruppel-Like Transcription Factors - chemistry ; Kruppel-Like Transcription Factors - metabolism ; Limb buds ; Mice ; Morphology ; Mutagenesis ; Mutation ; Mutation, Missense ; Nerve Tissue Proteins - chemistry ; Nerve Tissue Proteins - metabolism ; Physiological aspects ; Polydactyly ; Polydactyly - embryology ; Polydactyly - genetics ; Protein Stability ; Proteins ; Regulations ; Repressor Proteins - genetics ; Repressor Proteins - metabolism ; Signal transduction ; Signaling ; Stem cells ; Threonine - metabolism ; Transcription factors ; Zinc Finger Protein Gli2 ; Zinc Finger Protein Gli3</subject><ispartof>PloS one, 2015-03, Vol.10 (3), p.e0119455</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Makino et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Makino et al 2015 Makino et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-99b0ab1599d7c8c94197ec7422d4d959ff2848f06e9890d5fd44d82ce47ef1cc3</citedby><cites>FETCH-LOGICAL-c758t-99b0ab1599d7c8c94197ec7422d4d959ff2848f06e9890d5fd44d82ce47ef1cc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356511/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356511/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25760946$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Fernandez-Zapico, Martin</contributor><creatorcontrib>Makino, Shigeru</creatorcontrib><creatorcontrib>Zhulyn, Olena</creatorcontrib><creatorcontrib>Mo, Rong</creatorcontrib><creatorcontrib>Puviindran, Vijitha</creatorcontrib><creatorcontrib>Zhang, Xiaoyun</creatorcontrib><creatorcontrib>Murata, Takuya</creatorcontrib><creatorcontrib>Fukumura, Ryutaro</creatorcontrib><creatorcontrib>Ishitsuka, Yuichi</creatorcontrib><creatorcontrib>Kotaki, Hayato</creatorcontrib><creatorcontrib>Matsumaru, Daisuke</creatorcontrib><creatorcontrib>Ishii, Shunsuke</creatorcontrib><creatorcontrib>Hui, Chi-Chung</creatorcontrib><creatorcontrib>Gondo, Yoichi</creatorcontrib><title>T396I mutation of mouse Sufu reduces the stability and activity of Gli3 repressor</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Hedgehog signaling is primarily transduced by two transcription factors: Gli2, which mainly acts as a full-length activator, and Gli3, which tends to be proteolytically processed from a full-length form (Gli3FL) to an N-terminal repressor (Gli3REP). Recent studies using a Sufu knockout mouse have indicated that Sufu is involved in regulating Gli2 and Gli3 activator and repressor activity at multiple steps of the signaling cascade; however, the mechanism of specific Gli2 and Gli3 regulation remains to be elucidated. In this study, we established an allelic series of ENU-induced mouse strains. Analysis of one of the missense alleles, SufuT396I, showed that Thr396 residue of Sufu played a key role in regulation of Gli3 activity. SufuT396I/T396I embryos exhibited severe polydactyly, which is indicative of compromised Gli3 activity. Concomitantly, significant quantitative reductions of unprocessed Gli3 (Gli3FL) and processed Gli3 (Gli3REP) were observed in vivo as well as in vitro. Genetic experiments showed that patterning defects in the limb buds of SufuT396I/T396I were rescued by a constitutive Gli3REP allele (Gli3∆699), strongly suggesting that SufuT396I reduced the truncated Gli3 repressor. In contrast, SufuT396I qualitatively exhibited no mutational effects on Gli2 regulation. Taken together, the results of this study show that the Thr396 residue of Sufu is specifically required for regulation of Gli3 but not Gli2. This implies a novel Sufu-mediated mechanism in which Gli2 activator and Gli3 repressor are differentially regulated.</description><subject>Alleles</subject><subject>Animals</subject><subject>Biology</subject><subject>Body Patterning</subject><subject>Cellular signal transduction</subject><subject>Defects</subject><subject>Drosophila</subject><subject>Embryos</subject><subject>Ethyl nitrosourea</subject><subject>Extremities - growth & development</subject><subject>Gene mutation</subject><subject>Genetic aspects</subject><subject>Genetics</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Hedgehog protein</subject><subject>Hospitals</subject><subject>Insects</subject><subject>Isoleucine - metabolism</subject><subject>Kinases</subject><subject>Kruppel-Like Transcription Factors - chemistry</subject><subject>Kruppel-Like Transcription Factors - metabolism</subject><subject>Limb buds</subject><subject>Mice</subject><subject>Morphology</subject><subject>Mutagenesis</subject><subject>Mutation</subject><subject>Mutation, Missense</subject><subject>Nerve Tissue Proteins - chemistry</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Physiological aspects</subject><subject>Polydactyly</subject><subject>Polydactyly - embryology</subject><subject>Polydactyly - genetics</subject><subject>Protein Stability</subject><subject>Proteins</subject><subject>Regulations</subject><subject>Repressor Proteins - genetics</subject><subject>Repressor Proteins - metabolism</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Stem cells</subject><subject>Threonine - metabolism</subject><subject>Transcription factors</subject><subject>Zinc Finger Protein Gli2</subject><subject>Zinc Finger Protein Gli3</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkltrFDEYhgdR7EH_geiAUPBi15wzuRFK0bpQKNrqbcjmsJtlZrJNMsX-e7PutOyAguQip-d98_Hlrao3EMwh5vDjJgyxV-18G3o7BxAKQumz6hgKjGYMAfz8YH1UnaS0AYDihrGX1RGinAFB2HH17RYLtqi7IavsQ18HV3dhSLa-GdxQR2sGbVOd17ZOWS196_NDrXpTK539_W5TBJetxwXdRptSiK-qF061yb4e59Pqx5fPtxdfZ1fXl4uL86uZ5rTJMyGWQC0hFcJw3WhBoOBWc4KQIUZQ4RxqSOMAs6IRwFBnCDEN0pZw66DW-LR6t_fdtiHJsRtJQsYQQYxBXIjFnjBBbeQ2-k7FBxmUl38OQlxJFbPXrZUUM2aMU66UQgg1S8YVAqrB3ADGHSten8bXhmVnjbZ9jqqdmE5ver-Wq3AvCaaMQlgM3o8GMdwNNuV_lDxSK1Wq8r0LxUx3Pml5TlBT_lMIWqj5X6gyjO28LnlwvpxPBB8mgsJk-yuv1JCSXNx8_3_2-ueUPTtg11a1eZ1CO-yilKYg2YM6hpSidU-dg0Du4vzYDbmLsxzjXGRvD7v-JHrML_4NRcvvWA</recordid><startdate>20150311</startdate><enddate>20150311</enddate><creator>Makino, Shigeru</creator><creator>Zhulyn, Olena</creator><creator>Mo, Rong</creator><creator>Puviindran, Vijitha</creator><creator>Zhang, Xiaoyun</creator><creator>Murata, Takuya</creator><creator>Fukumura, Ryutaro</creator><creator>Ishitsuka, Yuichi</creator><creator>Kotaki, Hayato</creator><creator>Matsumaru, Daisuke</creator><creator>Ishii, Shunsuke</creator><creator>Hui, Chi-Chung</creator><creator>Gondo, Yoichi</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150311</creationdate><title>T396I mutation of mouse Sufu reduces the stability and activity of Gli3 repressor</title><author>Makino, Shigeru ; Zhulyn, Olena ; Mo, Rong ; Puviindran, Vijitha ; Zhang, Xiaoyun ; Murata, Takuya ; Fukumura, Ryutaro ; Ishitsuka, Yuichi ; Kotaki, Hayato ; Matsumaru, Daisuke ; Ishii, Shunsuke ; Hui, Chi-Chung ; Gondo, Yoichi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-99b0ab1599d7c8c94197ec7422d4d959ff2848f06e9890d5fd44d82ce47ef1cc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Alleles</topic><topic>Animals</topic><topic>Biology</topic><topic>Body Patterning</topic><topic>Cellular signal transduction</topic><topic>Defects</topic><topic>Drosophila</topic><topic>Embryos</topic><topic>Ethyl nitrosourea</topic><topic>Extremities - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Makino, Shigeru</au><au>Zhulyn, Olena</au><au>Mo, Rong</au><au>Puviindran, Vijitha</au><au>Zhang, Xiaoyun</au><au>Murata, Takuya</au><au>Fukumura, Ryutaro</au><au>Ishitsuka, Yuichi</au><au>Kotaki, Hayato</au><au>Matsumaru, Daisuke</au><au>Ishii, Shunsuke</au><au>Hui, Chi-Chung</au><au>Gondo, Yoichi</au><au>Fernandez-Zapico, Martin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>T396I mutation of mouse Sufu reduces the stability and activity of Gli3 repressor</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-03-11</date><risdate>2015</risdate><volume>10</volume><issue>3</issue><spage>e0119455</spage><pages>e0119455-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Hedgehog signaling is primarily transduced by two transcription factors: Gli2, which mainly acts as a full-length activator, and Gli3, which tends to be proteolytically processed from a full-length form (Gli3FL) to an N-terminal repressor (Gli3REP). Recent studies using a Sufu knockout mouse have indicated that Sufu is involved in regulating Gli2 and Gli3 activator and repressor activity at multiple steps of the signaling cascade; however, the mechanism of specific Gli2 and Gli3 regulation remains to be elucidated. In this study, we established an allelic series of ENU-induced mouse strains. Analysis of one of the missense alleles, SufuT396I, showed that Thr396 residue of Sufu played a key role in regulation of Gli3 activity. SufuT396I/T396I embryos exhibited severe polydactyly, which is indicative of compromised Gli3 activity. Concomitantly, significant quantitative reductions of unprocessed Gli3 (Gli3FL) and processed Gli3 (Gli3REP) were observed in vivo as well as in vitro. Genetic experiments showed that patterning defects in the limb buds of SufuT396I/T396I were rescued by a constitutive Gli3REP allele (Gli3∆699), strongly suggesting that SufuT396I reduced the truncated Gli3 repressor. In contrast, SufuT396I qualitatively exhibited no mutational effects on Gli2 regulation. Taken together, the results of this study show that the Thr396 residue of Sufu is specifically required for regulation of Gli3 but not Gli2. This implies a novel Sufu-mediated mechanism in which Gli2 activator and Gli3 repressor are differentially regulated.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25760946</pmid><doi>10.1371/journal.pone.0119455</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-03, Vol.10 (3), p.e0119455 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1662426613 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Alleles Animals Biology Body Patterning Cellular signal transduction Defects Drosophila Embryos Ethyl nitrosourea Extremities - growth & development Gene mutation Genetic aspects Genetics Genomes Genomics Hedgehog protein Hospitals Insects Isoleucine - metabolism Kinases Kruppel-Like Transcription Factors - chemistry Kruppel-Like Transcription Factors - metabolism Limb buds Mice Morphology Mutagenesis Mutation Mutation, Missense Nerve Tissue Proteins - chemistry Nerve Tissue Proteins - metabolism Physiological aspects Polydactyly Polydactyly - embryology Polydactyly - genetics Protein Stability Proteins Regulations Repressor Proteins - genetics Repressor Proteins - metabolism Signal transduction Signaling Stem cells Threonine - metabolism Transcription factors Zinc Finger Protein Gli2 Zinc Finger Protein Gli3 |
| title | T396I mutation of mouse Sufu reduces the stability and activity of Gli3 repressor |
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