Conditional Gata2 inactivation results in HSC loss and lymphatic mispatterning
Identifieur interne : 002F18 ( Pmc/Curation ); précédent : 002F17; suivant : 002F19Conditional Gata2 inactivation results in HSC loss and lymphatic mispatterning
Auteurs : Kim-Chew Lim ; Tomonori Hosoya ; William Brandt ; Chia-Jui Ku ; Sakie Hosoya-Ohmura ; Sally A. Camper [États-Unis] ; Masayuki Yamamoto [Japon] ; James Douglas EngelSource :
- The Journal of Clinical Investigation [ 0021-9738 ] ; 2012.
Abstract
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
Url:
DOI: 10.1172/JCI61619
PubMed: 22996665
PubMed Central: 3461906
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inactivation results in HSC loss and lymphatic mispatterning
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<series><title level="j">The Journal of Clinical Investigation</title>
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<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>
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<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>
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<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>
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<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>
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</contrib>
<contrib contrib-type="author"><name><surname>Yamamoto</surname>
<given-names>Masayuki</given-names>
</name>
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<contrib contrib-type="author"><name><surname>Engel</surname>
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<xref ref-type="aff" rid="JCI61619">1</xref>
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</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>
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<pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
. </pmc-comment>
<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.
</p>
</abstract>
</article-meta>
</front>
</pmc>
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