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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">UG4 Enhancer-Driven GATA-2 and Bone Morphogenetic Protein 4 Complementation Remedies the CAKUT Phenotype in <italic>Gata2</italic> Hypomorphic Mutant Mice</title><author><name sortKey="Ainoya, Keiko" sort="Ainoya, Keiko" uniqKey="Ainoya K" first="Keiko" last="Ainoya">Keiko Ainoya</name><affiliation><nlm:aff id="aff1">Department of Medical Biochemistry</nlm:aff></affiliation></author><author><name sortKey="Moriguchi, Takashi" sort="Moriguchi, Takashi" uniqKey="Moriguchi T" first="Takashi" last="Moriguchi">Takashi Moriguchi</name><affiliation><nlm:aff id="aff1">Department of Medical Biochemistry</nlm:aff></affiliation></author><author><name sortKey="Ohmori, Shin Ya" sort="Ohmori, Shin Ya" uniqKey="Ohmori S" first="Shin'Ya" last="Ohmori">Shin'Ya Ohmori</name><affiliation><nlm:aff id="aff1">Department of Medical Biochemistry</nlm:aff></affiliation></author><author><name sortKey="Souma, Tomokazu" sort="Souma, Tomokazu" uniqKey="Souma T" first="Tomokazu" last="Souma">Tomokazu Souma</name><affiliation><nlm:aff id="aff1">Department of Medical Biochemistry</nlm:aff></affiliation></author><author><name sortKey="Takai, Jun" sort="Takai, Jun" uniqKey="Takai J" first="Jun" last="Takai">Jun Takai</name><affiliation><nlm:aff id="aff1">Department of Medical Biochemistry</nlm:aff></affiliation></author><author><name sortKey="Morita, Masanobu" sort="Morita, Masanobu" uniqKey="Morita M" first="Masanobu" last="Morita">Masanobu Morita</name><affiliation><nlm:aff id="aff1">Department of Medical Biochemistry</nlm:aff></affiliation></author><author><name sortKey="Chandler, Kelly J" sort="Chandler, Kelly J" uniqKey="Chandler K" first="Kelly J." last="Chandler">Kelly J. Chandler</name><affiliation><nlm:aff id="aff4">Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee, USA</nlm:aff></affiliation></author><author><name sortKey="Mortlock, Douglas P" sort="Mortlock, Douglas P" uniqKey="Mortlock D" first="Douglas P." last="Mortlock">Douglas P. Mortlock</name><affiliation><nlm:aff id="aff4">Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee, USA</nlm:aff></affiliation></author><author><name sortKey="Shimizu, Ritsuko" sort="Shimizu, Ritsuko" uniqKey="Shimizu R" first="Ritsuko" last="Shimizu">Ritsuko Shimizu</name><affiliation><nlm:aff id="aff2">Department of Molecular Hematology, Tohoku University Graduate School of Medicine, Sendai, Japan</nlm:aff></affiliation></author><author><name sortKey="Engel, James Douglas" sort="Engel, James Douglas" uniqKey="Engel J" first="James Douglas" last="Engel">James Douglas Engel</name><affiliation><nlm:aff id="aff3">Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA</nlm:aff></affiliation></author><author><name sortKey="Lim, Kim Chew" sort="Lim, Kim Chew" uniqKey="Lim K" first="Kim-Chew" last="Lim">Kim-Chew Lim</name><affiliation><nlm:aff id="aff3">Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA</nlm:aff></affiliation></author><author><name sortKey="Yamamoto, Masayuki" sort="Yamamoto, Masayuki" uniqKey="Yamamoto M" first="Masayuki" last="Yamamoto">Masayuki Yamamoto</name><affiliation><nlm:aff id="aff1">Department of Medical Biochemistry</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22493062</idno><idno type="pmc">3372261</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3372261</idno><idno type="RBID">PMC:3372261</idno><idno type="doi">10.1128/MCB.06699-11</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">003086</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">003086</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">UG4 Enhancer-Driven GATA-2 and Bone Morphogenetic Protein 4 Complementation Remedies the CAKUT Phenotype in <italic>Gata2</italic> Hypomorphic Mutant Mice</title><author><name sortKey="Ainoya, Keiko" sort="Ainoya, Keiko" uniqKey="Ainoya K" first="Keiko" last="Ainoya">Keiko Ainoya</name><affiliation><nlm:aff id="aff1">Department of Medical Biochemistry</nlm:aff></affiliation></author><author><name sortKey="Moriguchi, Takashi" sort="Moriguchi, Takashi" uniqKey="Moriguchi T" first="Takashi" last="Moriguchi">Takashi Moriguchi</name><affiliation><nlm:aff id="aff1">Department of Medical Biochemistry</nlm:aff></affiliation></author><author><name sortKey="Ohmori, Shin Ya" sort="Ohmori, Shin Ya" uniqKey="Ohmori S" first="Shin'Ya" last="Ohmori">Shin'Ya Ohmori</name><affiliation><nlm:aff id="aff1">Department of Medical Biochemistry</nlm:aff></affiliation></author><author><name sortKey="Souma, Tomokazu" sort="Souma, Tomokazu" uniqKey="Souma T" first="Tomokazu" last="Souma">Tomokazu Souma</name><affiliation><nlm:aff id="aff1">Department of Medical Biochemistry</nlm:aff></affiliation></author><author><name sortKey="Takai, Jun" sort="Takai, Jun" uniqKey="Takai J" first="Jun" last="Takai">Jun Takai</name><affiliation><nlm:aff id="aff1">Department of Medical Biochemistry</nlm:aff></affiliation></author><author><name sortKey="Morita, Masanobu" sort="Morita, Masanobu" uniqKey="Morita M" first="Masanobu" last="Morita">Masanobu Morita</name><affiliation><nlm:aff id="aff1">Department of Medical Biochemistry</nlm:aff></affiliation></author><author><name sortKey="Chandler, Kelly J" sort="Chandler, Kelly J" uniqKey="Chandler K" first="Kelly J." last="Chandler">Kelly J. Chandler</name><affiliation><nlm:aff id="aff4">Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee, USA</nlm:aff></affiliation></author><author><name sortKey="Mortlock, Douglas P" sort="Mortlock, Douglas P" uniqKey="Mortlock D" first="Douglas P." last="Mortlock">Douglas P. Mortlock</name><affiliation><nlm:aff id="aff4">Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee, USA</nlm:aff></affiliation></author><author><name sortKey="Shimizu, Ritsuko" sort="Shimizu, Ritsuko" uniqKey="Shimizu R" first="Ritsuko" last="Shimizu">Ritsuko Shimizu</name><affiliation><nlm:aff id="aff2">Department of Molecular Hematology, Tohoku University Graduate School of Medicine, Sendai, Japan</nlm:aff></affiliation></author><author><name sortKey="Engel, James Douglas" sort="Engel, James Douglas" uniqKey="Engel J" first="James Douglas" last="Engel">James Douglas Engel</name><affiliation><nlm:aff id="aff3">Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA</nlm:aff></affiliation></author><author><name sortKey="Lim, Kim Chew" sort="Lim, Kim Chew" uniqKey="Lim K" first="Kim-Chew" last="Lim">Kim-Chew Lim</name><affiliation><nlm:aff id="aff3">Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA</nlm:aff></affiliation></author><author><name sortKey="Yamamoto, Masayuki" sort="Yamamoto, Masayuki" uniqKey="Yamamoto M" first="Masayuki" last="Yamamoto">Masayuki Yamamoto</name><affiliation><nlm:aff id="aff1">Department of Medical Biochemistry</nlm:aff></affiliation></author></analytic><series><title level="j">Molecular and Cellular Biology</title><idno type="ISSN">0270-7306</idno><idno type="eISSN">1098-5549</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>During renal development, the proper emergence of the ureteric bud (UB) from the Wolffian duct is essential for formation of the urinary system. Previously, we showed that expression of transcription factor GATA-2 in the urogenital primordium was demarcated anteroposteriorly into two domains that were regulated by separate enhancers. While GATA-2 expression in the caudal urogenital mesenchyme is controlled by the UG4 enhancer, its more-rostral expression is regulated by UG2. We found that anteriorly displaced budding led to obstructed megaureters in <italic>Gata2</italic> hypomorphic mutant mice, possibly due to reduced expression of the downstream effector bone morphogenetic protein 4 (BMP4). Here, we report that UG4-driven, but not UG2-driven, GATA-2 expression in the urogenital mesenchyme significantly reverts the uropathy observed in the <italic>Gata2</italic> hypomorphic mutant mice. Furthermore, the data show that transgenic rescue by GATA-2 reverses the rostral outgrowth of the UB. We also provide evidence for a GATA-2–BMP4 epistatic relationship by demonstrating that reporter gene expression from a <italic>Bmp4</italic> bacterial artificial chromosome (BAC) transgene is altered in <italic>Gata2</italic> hypomorphs; furthermore, UG4-directed BMP4 expression in the mutants leads to reduced incidence of megaureters. These results demonstrate that GATA-2 expression in the caudal urogenital mesenchyme as directed by the UG4 enhancer is crucial for proper development of the urinary tract and that its regulation of BMP4 expression is a critical aspect of this function.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Mol Cell Biol</journal-id><journal-id journal-id-type="iso-abbrev">Mol. Cell. Biol</journal-id><journal-id journal-id-type="hwp">mcb</journal-id><journal-id journal-id-type="pmc">mcb</journal-id><journal-id journal-id-type="publisher-id">MCB</journal-id><journal-title-group><journal-title>Molecular and Cellular Biology</journal-title></journal-title-group><issn pub-type="ppub">0270-7306</issn><issn pub-type="epub">1098-5549</issn><publisher><publisher-name>American Society for Microbiology</publisher-name><publisher-loc>1752 N St., N.W., Washington, DC</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">22493062</article-id><article-id pub-id-type="pmc">3372261</article-id><article-id pub-id-type="publisher-id">06699-11</article-id><article-id pub-id-type="doi">10.1128/MCB.06699-11</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group></article-categories><title-group><article-title>UG4 Enhancer-Driven GATA-2 and Bone Morphogenetic Protein 4 Complementation Remedies the CAKUT Phenotype in <italic>Gata2</italic> Hypomorphic Mutant Mice</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Ainoya</surname><given-names>Keiko</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Moriguchi</surname><given-names>Takashi</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ohmori</surname><given-names>Shin'ya</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Souma</surname><given-names>Tomokazu</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Takai</surname><given-names>Jun</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Morita</surname><given-names>Masanobu</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chandler</surname><given-names>Kelly J.</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mortlock</surname><given-names>Douglas P.</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Shimizu</surname><given-names>Ritsuko</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Engel</surname><given-names>James Douglas</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lim</surname><given-names>Kim-Chew</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Yamamoto</surname><given-names>Masayuki</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><aff id="aff1"><label>a</label>Department of Medical Biochemistry</aff><aff id="aff2"><label>b</label>Department of Molecular Hematology, Tohoku University Graduate School of Medicine, Sendai, Japan</aff><aff id="aff3"><label>c</label>Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA</aff><aff id="aff4"><label>d</label>Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee, USA</aff></contrib-group><author-notes><corresp>Address correspondence to Masayuki Yamamoto, <email>masiyamamoto@med.tohoku.ac.jp</email>, or Takashi Moriguchi, <email>moriguch@med.tohoku.ac.jp</email>.</corresp></author-notes><pub-date pub-type="ppub"><month>6</month><year>2012</year></pub-date><volume>32</volume><issue>12</issue><fpage>2312</fpage><lpage>2322</lpage><history><date date-type="received"><day>16</day><month>12</month><year>2011</year></date><date date-type="rev-request"><day>4</day><month>1</month><year>2012</year></date><date date-type="accepted"><day>30</day><month>3</month><year>2012</year></date></history><permissions><copyright-statement>Copyright © 2012, American Society for Microbiology. All Rights Reserved.</copyright-statement><copyright-year>2012</copyright-year><copyright-holder>American Society for Microbiology</copyright-holder></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zmb01212002312.pdf"></self-uri><abstract><p>During renal development, the proper emergence of the ureteric bud (UB) from the Wolffian duct is essential for formation of the urinary system. Previously, we showed that expression of transcription factor GATA-2 in the urogenital primordium was demarcated anteroposteriorly into two domains that were regulated by separate enhancers. While GATA-2 expression in the caudal urogenital mesenchyme is controlled by the UG4 enhancer, its more-rostral expression is regulated by UG2. We found that anteriorly displaced budding led to obstructed megaureters in <italic>Gata2</italic> hypomorphic mutant mice, possibly due to reduced expression of the downstream effector bone morphogenetic protein 4 (BMP4). Here, we report that UG4-driven, but not UG2-driven, GATA-2 expression in the urogenital mesenchyme significantly reverts the uropathy observed in the <italic>Gata2</italic> hypomorphic mutant mice. Furthermore, the data show that transgenic rescue by GATA-2 reverses the rostral outgrowth of the UB. We also provide evidence for a GATA-2–BMP4 epistatic relationship by demonstrating that reporter gene expression from a <italic>Bmp4</italic> bacterial artificial chromosome (BAC) transgene is altered in <italic>Gata2</italic> hypomorphs; furthermore, UG4-directed BMP4 expression in the mutants leads to reduced incidence of megaureters. These results demonstrate that GATA-2 expression in the caudal urogenital mesenchyme as directed by the UG4 enhancer is crucial for proper development of the urinary tract and that its regulation of BMP4 expression is a critical aspect of this function.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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