Foxc1 and Foxc2 deletion causes abnormal lymphangiogenesis and correlates with ERK hyperactivation
Identifieur interne : 000674 ( Pmc/Curation ); précédent : 000673; suivant : 000675Foxc1 and Foxc2 deletion causes abnormal lymphangiogenesis and correlates with ERK hyperactivation
Auteurs : Anees Fatima [États-Unis] ; Ying Wang [États-Unis] ; Yutaka Uchida [États-Unis] ; Pieter Norden [États-Unis] ; Ting Liu [États-Unis] ; Austin Culver [États-Unis] ; William H. Dietz [États-Unis] ; Ford Culver [États-Unis] ; Meredith Millay [États-Unis] ; Yoh-Suke Mukouyama [États-Unis] ; Tsutomu Kume [États-Unis]Source :
- The Journal of Clinical Investigation [ 0021-9738 ] ; ????.
Abstract
The lymphatic vasculature is essential for maintaining interstitial fluid homeostasis, and dysfunctional lymphangiogenesis contributes to various pathological processes, including inflammatory disease and tumor metastasis. Mutations in
Url:
DOI: 10.1172/JCI80465
PubMed: 27214551
PubMed Central: 4922698
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>Foxc1</italic>
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deletion causes abnormal lymphangiogenesis and correlates with ERK hyperactivation</title>
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<author><name sortKey="Wang, Ying" sort="Wang, Ying" uniqKey="Wang Y" first="Ying" last="Wang">Ying Wang</name>
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<author><name sortKey="Uchida, Yutaka" sort="Uchida, Yutaka" uniqKey="Uchida Y" first="Yutaka" last="Uchida">Yutaka Uchida</name>
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<author><name sortKey="Culver, Austin" sort="Culver, Austin" uniqKey="Culver A" first="Austin" last="Culver">Austin Culver</name>
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<author><name sortKey="Culver, Ford" sort="Culver, Ford" uniqKey="Culver F" first="Ford" last="Culver">Ford Culver</name>
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<author><name sortKey="Millay, Meredith" sort="Millay, Meredith" uniqKey="Millay M" first="Meredith" last="Millay">Meredith Millay</name>
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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 lymphatic vasculature is essential for maintaining interstitial fluid homeostasis, and dysfunctional lymphangiogenesis contributes to various pathological processes, including inflammatory disease and tumor metastasis. Mutations in <italic>FOXC2</italic>
are dominantly associated with late-onset lymphedema; however, the precise role of FOXC2 and a closely related factor, FOXC1, in the lymphatic system remains largely unknown. Here we identified a molecular cascade by which FOXC1 and FOXC2 regulate ERK signaling in lymphatic vessel growth. In mice, lymphatic endothelial cell–specific (LEC-specific) deletion of <italic>Foxc1</italic>
, <italic>Foxc2</italic>
, or both resulted in increased LEC proliferation, enlarged lymphatic vessels, and abnormal lymphatic vessel morphogenesis. Compared with LECs from control animals, LECs from mice lacking both <italic>Foxc1</italic>
and <italic>Foxc2</italic>
exhibited aberrant expression of Ras regulators, and embryos with LEC-specific deletion of <italic>Foxc1</italic>
and <italic>Foxc2</italic>
, alone or in combination, exhibited ERK hyperactivation. Pharmacological ERK inhibition in utero abolished the abnormally enlarged lymphatic vessels in FOXC-deficient embryos. Together, these results identify FOXC1 and FOXC2 as essential regulators of lymphangiogenesis and indicate a new potential mechanistic basis for lymphatic-associated diseases.</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">27214551</article-id>
<article-id pub-id-type="pmc">4922698</article-id>
<article-id pub-id-type="publisher-id">80465</article-id>
<article-id pub-id-type="doi">10.1172/JCI80465</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
</article-categories>
<title-group><article-title><italic>Foxc1</italic>
and <italic>Foxc2</italic>
deletion causes abnormal lymphangiogenesis and correlates with ERK hyperactivation</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Fatima</surname>
<given-names>Anees</given-names>
</name>
<email>a-fatima@northwestern.edu</email>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wang</surname>
<given-names>Ying</given-names>
</name>
<email>Wang.Ying@mayo.edu</email>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Uchida</surname>
<given-names>Yutaka</given-names>
</name>
<email>uchiday@nhlbi.nih.gov</email>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Norden</surname>
<given-names>Pieter</given-names>
</name>
<email>pieter.norden@northwestern.edu</email>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Liu</surname>
<given-names>Ting</given-names>
</name>
<email>ting-liu@northwestern.edu</email>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Culver</surname>
<given-names>Austin</given-names>
</name>
<email>austin.culver@gmail.com</email>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dietz</surname>
<given-names>William H.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Culver</surname>
<given-names>Ford</given-names>
</name>
<email>fordculver@gmail.com</email>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Millay</surname>
<given-names>Meredith</given-names>
</name>
<email>merandturtle@gmail.com</email>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mukouyama</surname>
<given-names>Yoh-suke</given-names>
</name>
<email>mukoyamay@nhlbi.nih.gov</email>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Kume</surname>
<given-names>Tsutomu</given-names>
</name>
<email>t-kume@northwestern.edu</email>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Feinberg Cardiovascular Research Institute, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.</aff>
<aff id="A2"><label>2</label>
Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA.</aff>
<aff id="A3"><label>3</label>
Laboratory of Stem Cell and Neuro-Vascular Biology, Genetics and Developmental Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.</aff>
<author-notes><corresp>Address correspondence to: Tsutomu Kume, Feinberg Cardiovascular Research Institute, Department of Medicine, Northwestern University School of Medicine, 300 E Superior Street, Chicago, Illinois 60611, USA. Phone: 312.503.0623; E-mail: <email>t-kume@northwestern.edu</email>
.</corresp>
</author-notes>
<pub-date date-type="pub" publication-format="electronic" iso-8601-date="2016-05-23"><day>23</day>
<month>5</month>
<year>2016</year>
</pub-date>
<pub-date date-type="pub" publication-format="print" iso-8601-date="2016-07-01"><day>1</day>
<month>7</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>1</day>
<month>10</month>
<year>2016</year>
</pub-date>
<pmc-comment> PMC Release delay is 3 months and
0 days and was based on the . </pmc-comment>
<volume>126</volume>
<issue>7</issue>
<fpage>2437</fpage>
<lpage>2451</lpage>
<history><date date-type="received"><day>15</day>
<month>12</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>5</day>
<month>4</month>
<year>2016</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2016, American Society for Clinical Investigation</copyright-statement>
<copyright-year>2016</copyright-year>
<copyright-holder>American Society for Clinical Investigation</copyright-holder>
</permissions>
<self-uri xlink:href="https://www.jci.org/articles/view/80465">This article is available online at https://www.jci.org/articles/view/80465</self-uri>
<abstract><p>The lymphatic vasculature is essential for maintaining interstitial fluid homeostasis, and dysfunctional lymphangiogenesis contributes to various pathological processes, including inflammatory disease and tumor metastasis. Mutations in <italic>FOXC2</italic>
are dominantly associated with late-onset lymphedema; however, the precise role of FOXC2 and a closely related factor, FOXC1, in the lymphatic system remains largely unknown. Here we identified a molecular cascade by which FOXC1 and FOXC2 regulate ERK signaling in lymphatic vessel growth. In mice, lymphatic endothelial cell–specific (LEC-specific) deletion of <italic>Foxc1</italic>
, <italic>Foxc2</italic>
, or both resulted in increased LEC proliferation, enlarged lymphatic vessels, and abnormal lymphatic vessel morphogenesis. Compared with LECs from control animals, LECs from mice lacking both <italic>Foxc1</italic>
and <italic>Foxc2</italic>
exhibited aberrant expression of Ras regulators, and embryos with LEC-specific deletion of <italic>Foxc1</italic>
and <italic>Foxc2</italic>
, alone or in combination, exhibited ERK hyperactivation. Pharmacological ERK inhibition in utero abolished the abnormally enlarged lymphatic vessels in FOXC-deficient embryos. Together, these results identify FOXC1 and FOXC2 as essential regulators of lymphangiogenesis and indicate a new potential mechanistic basis for lymphatic-associated diseases.</p>
</abstract>
</article-meta>
</front>
</pmc>
</record>
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