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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Conditional <italic>Gata2</italic> inactivation results in HSC loss and lymphatic mispatterning
</title><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 wicri:cut=" and" id="JCI61619">Department of Cell and Developmental Biology</nlm:aff></affiliation></author><author><name sortKey="Hosoya, Tomonori" sort="Hosoya, Tomonori" uniqKey="Hosoya T" first="Tomonori" last="Hosoya">Tomonori Hosoya</name><affiliation><nlm:aff wicri:cut=" and" id="JCI61619">Department of Cell and Developmental Biology</nlm:aff></affiliation></author><author><name sortKey="Brandt, William" sort="Brandt, William" uniqKey="Brandt W" first="William" last="Brandt">William Brandt</name><affiliation><nlm:aff wicri:cut=" and" id="JCI61619">Department of Cell and Developmental Biology</nlm:aff></affiliation></author><author><name sortKey="Ku, Chia Jui" sort="Ku, Chia Jui" uniqKey="Ku C" first="Chia-Jui" last="Ku">Chia-Jui Ku</name><affiliation><nlm:aff wicri:cut=" and" id="JCI61619">Department of Cell and Developmental Biology</nlm:aff></affiliation></author><author><name sortKey="Hosoya Ohmura, Sakie" sort="Hosoya Ohmura, Sakie" uniqKey="Hosoya Ohmura S" first="Sakie" last="Hosoya-Ohmura">Sakie Hosoya-Ohmura</name><affiliation><nlm:aff wicri:cut=" and" id="JCI61619">Department of Cell and Developmental Biology</nlm:aff></affiliation></author><author><name sortKey="Camper, Sally A" sort="Camper, Sally A" uniqKey="Camper S" first="Sally A." last="Camper">Sally A. Camper</name><affiliation><nlm:aff id="JCI61619">Department of Human Genetics, University of Michigan Medical School, 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="JCI61619">Department of Medical Biochemistry, 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 wicri:cut=" and" id="JCI61619">Department of Cell and Developmental Biology</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22996665</idno><idno type="pmc">3461906</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461906</idno><idno type="RBID">PMC:3461906</idno><idno type="doi">10.1172/JCI61619</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">002F19</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002F19</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Conditional <italic>Gata2</italic> inactivation results in HSC loss and lymphatic mispatterning
</title><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 wicri:cut=" and" id="JCI61619">Department of Cell and Developmental Biology</nlm:aff></affiliation></author><author><name sortKey="Hosoya, Tomonori" sort="Hosoya, Tomonori" uniqKey="Hosoya T" first="Tomonori" last="Hosoya">Tomonori Hosoya</name><affiliation><nlm:aff wicri:cut=" and" id="JCI61619">Department of Cell and Developmental Biology</nlm:aff></affiliation></author><author><name sortKey="Brandt, William" sort="Brandt, William" uniqKey="Brandt W" first="William" last="Brandt">William Brandt</name><affiliation><nlm:aff wicri:cut=" and" id="JCI61619">Department of Cell and Developmental Biology</nlm:aff></affiliation></author><author><name sortKey="Ku, Chia Jui" sort="Ku, Chia Jui" uniqKey="Ku C" first="Chia-Jui" last="Ku">Chia-Jui Ku</name><affiliation><nlm:aff wicri:cut=" and" id="JCI61619">Department of Cell and Developmental Biology</nlm:aff></affiliation></author><author><name sortKey="Hosoya Ohmura, Sakie" sort="Hosoya Ohmura, Sakie" uniqKey="Hosoya Ohmura S" first="Sakie" last="Hosoya-Ohmura">Sakie Hosoya-Ohmura</name><affiliation><nlm:aff wicri:cut=" and" id="JCI61619">Department of Cell and Developmental Biology</nlm:aff></affiliation></author><author><name sortKey="Camper, Sally A" sort="Camper, Sally A" uniqKey="Camper S" first="Sally A." last="Camper">Sally A. Camper</name><affiliation><nlm:aff id="JCI61619">Department of Human Genetics, University of Michigan Medical School, 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="JCI61619">Department of Medical Biochemistry, 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 wicri:cut=" and" id="JCI61619">Department of Cell and Developmental Biology</nlm:aff></affiliation></author></analytic><series><title level="j">The Journal of Clinical Investigation</title><idno type="ISSN">0021-9738</idno><idno type="eISSN">1558-8238</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>The transcription factor GATA-2 plays vital roles in quite diverse developmental programs, including hematopoietic stem cell (HSC) survival and proliferation. We previously identified a vascular endothelial (VE) enhancer that regulates GATA-2 activity in pan-endothelial cells. To more thoroughly define the in vivo regulatory properties of this enhancer, we generated a tamoxifen-inducible Cre transgenic mouse line using the <italic>Gata2</italic> VE enhancer (<italic>Gata2</italic> VECre) and utilized it to temporally direct tissue-specific conditional loss of <italic>Gata2</italic>. Here, we report that <italic>Gata2</italic> VECre–mediated loss of GATA-2 led to anemia, hemorrhage, and eventual death in edematous embryos. We further determined that the etiology of anemia in conditional <italic>Gata2</italic> mutant embryos involved HSC loss in the fetal liver, as demonstrated by in vitro colony-forming and immunophenotypic as well as in vivo long-term competitive repopulation experiments. We further documented that the edema and hemorrhage in conditional <italic>Gata2</italic> mutant embryos were due to defective lymphatic development. Thus, we unexpectedly discovered that in addition to its contribution to endothelial cell development, the VE enhancer also regulates GATA-2 expression in definitive fetal liver and adult BM HSCs, and that GATA-2 function is required for proper lymphatic vascular development during embryogenesis.
</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">J Clin Invest</journal-id><journal-id journal-id-type="iso-abbrev">J. Clin. Invest</journal-id><journal-id journal-id-type="publisher-id">J CLIN INVEST</journal-id><journal-title-group><journal-title>The Journal of Clinical Investigation</journal-title></journal-title-group><issn pub-type="ppub">0021-9738</issn><issn pub-type="epub">1558-8238</issn><publisher><publisher-name>American Society for Clinical Investigation</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">22996665</article-id><article-id pub-id-type="pmc">3461906</article-id><article-id pub-id-type="publisher-id">61619</article-id><article-id pub-id-type="doi">10.1172/JCI61619</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>Conditional <italic>Gata2</italic> inactivation results in HSC loss and lymphatic mispatterning
</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Lim</surname><given-names>Kim-Chew</given-names></name><xref ref-type="aff" rid="JCI61619">1</xref></contrib><contrib contrib-type="author"><name><surname>Hosoya</surname><given-names>Tomonori</given-names></name><xref ref-type="aff" rid="JCI61619">1</xref></contrib><contrib contrib-type="author"><name><surname>Brandt</surname><given-names>William</given-names></name><xref ref-type="aff" rid="JCI61619">1</xref></contrib><contrib contrib-type="author"><name><surname>Ku</surname><given-names>Chia-Jui</given-names></name><xref ref-type="aff" rid="JCI61619">1</xref></contrib><contrib contrib-type="author"><name><surname>Hosoya-Ohmura</surname><given-names>Sakie</given-names></name><xref ref-type="aff" rid="JCI61619">1</xref></contrib><contrib contrib-type="author"><name><surname>Camper</surname><given-names>Sally A.</given-names></name><xref ref-type="aff" rid="JCI61619">2</xref></contrib><contrib contrib-type="author"><name><surname>Yamamoto</surname><given-names>Masayuki</given-names></name><xref ref-type="aff" rid="JCI61619">3</xref></contrib><contrib contrib-type="author"><name><surname>Engel</surname><given-names>James Douglas</given-names></name><xref ref-type="aff" rid="JCI61619">1</xref></contrib></contrib-group><aff id="JCI61619"><label>1</label>Department of Cell and Developmental Biology and<label>2</label>Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA.<label>3</label>Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.</aff><author-notes><corresp>Address correspondence to: James Douglas Engel, The University of Michigan Medical School, Cell and Developmental Biology, 109 Zina Pitcher Place, 3072 BSRB, Ann Arbor, Michigan 48109-2200, USA. Phone: 734.615.7509; Fax: 734.615.8500; E-mail:
<email>engel@umich.edu</email>.
</corresp></author-notes><pub-date pub-type="epub"><day>10</day><month>9</month><year>2012</year></pub-date><pub-date pub-type="ppub"><day>1</day><month>10</month><year>2012</year></pub-date><pub-date pub-type="pmc-release"><day>10</day><month>9</month><year>2012</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>122</volume><issue>10</issue><fpage>3705</fpage><lpage>3717</lpage><history><date date-type="received"><day>25</day><month>10</month><year>2011</year></date><date date-type="accepted"><day>19</day><month>7</month><year>2012</year></date></history><permissions><copyright-statement>Copyright © 2012, American Society for Clinical Investigation</copyright-statement><copyright-year>2012</copyright-year></permissions><abstract><p>The transcription factor GATA-2 plays vital roles in quite diverse developmental programs, including hematopoietic stem cell (HSC) survival and proliferation. We previously identified a vascular endothelial (VE) enhancer that regulates GATA-2 activity in pan-endothelial cells. To more thoroughly define the in vivo regulatory properties of this enhancer, we generated a tamoxifen-inducible Cre transgenic mouse line using the <italic>Gata2</italic> VE enhancer (<italic>Gata2</italic> VECre) and utilized it to temporally direct tissue-specific conditional loss of <italic>Gata2</italic>. Here, we report that <italic>Gata2</italic> VECre–mediated loss of GATA-2 led to anemia, hemorrhage, and eventual death in edematous embryos. We further determined that the etiology of anemia in conditional <italic>Gata2</italic> mutant embryos involved HSC loss in the fetal liver, as demonstrated by in vitro colony-forming and immunophenotypic as well as in vivo long-term competitive repopulation experiments. We further documented that the edema and hemorrhage in conditional <italic>Gata2</italic> mutant embryos were due to defective lymphatic development. Thus, we unexpectedly discovered that in addition to its contribution to endothelial cell development, the VE enhancer also regulates GATA-2 expression in definitive fetal liver and adult BM HSCs, and that GATA-2 function is required for proper lymphatic vascular development during embryogenesis.
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