Lymphatic regulator PROX1 determines Schlemm’s canal integrity and identity
Identifieur interne : 006893 ( Ncbi/Merge ); précédent : 006892; suivant : 006894Lymphatic regulator PROX1 determines Schlemm’s canal integrity and identity
Auteurs : Dae-Young Park [Corée du Sud] ; Junyeop Lee [Corée du Sud] ; Intae Park [Corée du Sud] ; Dongwon Choi [États-Unis] ; Sunju Lee [États-Unis] ; Sukhyun Song [Corée du Sud] ; Yoonha Hwang [Corée du Sud] ; Ki Yong Hong [Corée du Sud] ; Yoshikazu Nakaoka [Japon] ; Taija Makinen [Suède] ; Pilhan Kim [Corée du Sud] ; Kari Alitalo [Finlande] ; Young-Kwon Hong [États-Unis] ; Gou Young Koh [Corée du Sud]Source :
- The Journal of Clinical Investigation [ 0021-9738 ] ; 2014.
Abstract
Schlemm’s canal (SC) is a specialized vascular structure in the eye that functions to drain aqueous humor from the intraocular chamber into systemic circulation. Dysfunction of SC has been proposed to underlie increased aqueous humor outflow (AHO) resistance, which leads to elevated ocular pressure, a factor for glaucoma development in humans. Here, using lymphatic and blood vasculature reporter mice, we determined that SC, which originates from blood vessels during the postnatal period, acquires lymphatic identity through upregulation of prospero homeobox protein 1 (PROX1), the master regulator of lymphatic development. SC expressed lymphatic valve markers FOXC2 and integrin α9 and exhibited continuous vascular endothelial–cadherin (VE-cadherin) junctions and basement membrane, similar to collecting lymphatics. SC notably lacked luminal valves and expression of the lymphatic endothelial cell markers podoplanin and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1). Using an ocular puncture model, we determined that reduced AHO altered the fate of SC both during development and under pathologic conditions; however, alteration of VEGF-C/VEGFR3 signaling did not modulate SC integrity and identity. Intriguingly, PROX1 expression levels linearly correlated with SC functionality. For example, PROX1 expression was reduced or undetectable under pathogenic conditions and in deteriorated SCs. Collectively, our data indicate that PROX1 is an accurate and reliable biosensor of SC integrity and identity.
Url:
DOI: 10.1172/JCI75392
PubMed: 25061877
PubMed Central: 4153702
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<author><name sortKey="Hwang, Yoonha" sort="Hwang, Yoonha" uniqKey="Hwang Y" first="Yoonha" last="Hwang">Yoonha Hwang</name>
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<author><name sortKey="Nakaoka, Yoshikazu" sort="Nakaoka, Yoshikazu" uniqKey="Nakaoka Y" first="Yoshikazu" last="Nakaoka">Yoshikazu Nakaoka</name>
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<country xml:lang="fr" wicri:curation="lc">Japon</country>
<wicri:regionArea>Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka</wicri:regionArea>
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<author><name sortKey="Makinen, Taija" sort="Makinen, Taija" uniqKey="Makinen T" first="Taija" last="Makinen">Taija Makinen</name>
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<country xml:lang="fr" wicri:curation="lc">Suède</country>
<wicri:regionArea>Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala</wicri:regionArea>
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<author><name sortKey="Kim, Pilhan" sort="Kim, Pilhan" uniqKey="Kim P" first="Pilhan" last="Kim">Pilhan Kim</name>
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<author><name sortKey="Alitalo, Kari" sort="Alitalo, Kari" uniqKey="Alitalo K" first="Kari" last="Alitalo">Kari Alitalo</name>
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<country xml:lang="fr" wicri:curation="lc">Finlande</country>
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<author><name sortKey="Hong, Young Kwon" sort="Hong, Young Kwon" uniqKey="Hong Y" first="Young-Kwon" last="Hong">Young-Kwon Hong</name>
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<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Surgery, Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
<settlement type="city">Los Angeles</settlement>
</placeName>
<orgName type="university">Université de Californie du Sud</orgName>
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<author><name sortKey="Koh, Gou Young" sort="Koh, Gou Young" uniqKey="Koh G" first="Gou Young" last="Koh">Gou Young Koh</name>
<affiliation wicri:level="1"><nlm:aff id="JCI75392">National Research Laboratory of Vascular Biology and Stem Cells, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Corée du Sud</country>
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<wicri:noRegion>Daejeon</wicri:noRegion>
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<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="2014">2014</date>
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<front><div type="abstract" xml:lang="en"><p>Schlemm’s canal (SC) is a specialized vascular structure in the eye that functions
to drain aqueous humor from the intraocular chamber into systemic circulation. Dysfunction
of SC has been proposed to underlie increased aqueous humor outflow (AHO) resistance,
which leads to elevated ocular pressure, a factor for glaucoma development in humans.
Here, using lymphatic and blood vasculature reporter mice, we determined that SC, which
originates from blood vessels during the postnatal period, acquires lymphatic identity
through upregulation of prospero homeobox protein 1 (PROX1), the master regulator of
lymphatic development. SC expressed lymphatic valve markers FOXC2 and integrin
α<sub>9</sub>
and exhibited continuous vascular endothelial–cadherin
(VE-cadherin) junctions and basement membrane, similar to collecting lymphatics. SC
notably lacked luminal valves and expression of the lymphatic endothelial cell markers
podoplanin and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1). Using an
ocular puncture model, we determined that reduced AHO altered the fate of SC both during
development and under pathologic conditions; however, alteration of VEGF-C/VEGFR3
signaling did not modulate SC integrity and identity. Intriguingly, PROX1 expression
levels linearly correlated with SC functionality. For example, PROX1 expression was
reduced or undetectable under pathogenic conditions and in deteriorated SCs. Collectively,
our data indicate that PROX1 is an accurate and reliable biosensor of SC integrity and
identity.</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">25061877</article-id>
<article-id pub-id-type="pmc">4153702</article-id>
<article-id pub-id-type="publisher-id">75392</article-id>
<article-id pub-id-type="doi">10.1172/JCI75392</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Lymphatic regulator PROX1 determines Schlemm’s canal integrity and
identity</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Park</surname>
<given-names>Dae-Young</given-names>
</name>
<xref ref-type="aff" rid="JCI75392">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lee</surname>
<given-names>Junyeop</given-names>
</name>
<xref ref-type="aff" rid="JCI75392">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Park</surname>
<given-names>Intae</given-names>
</name>
<xref ref-type="aff" rid="JCI75392">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Choi</surname>
<given-names>Dongwon</given-names>
</name>
<xref ref-type="aff" rid="JCI75392">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lee</surname>
<given-names>Sunju</given-names>
</name>
<xref ref-type="aff" rid="JCI75392">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Song</surname>
<given-names>Sukhyun</given-names>
</name>
<xref ref-type="aff" rid="JCI75392">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hwang</surname>
<given-names>Yoonha</given-names>
</name>
<xref ref-type="aff" rid="JCI75392">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hong</surname>
<given-names>Ki Yong</given-names>
</name>
<xref ref-type="aff" rid="JCI75392">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Nakaoka</surname>
<given-names>Yoshikazu</given-names>
</name>
<xref ref-type="aff" rid="JCI75392">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Makinen</surname>
<given-names>Taija</given-names>
</name>
<xref ref-type="aff" rid="JCI75392">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kim</surname>
<given-names>Pilhan</given-names>
</name>
<xref ref-type="aff" rid="JCI75392">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Alitalo</surname>
<given-names>Kari</given-names>
</name>
<xref ref-type="aff" rid="JCI75392">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hong</surname>
<given-names>Young-Kwon</given-names>
</name>
<xref ref-type="aff" rid="JCI75392">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Koh</surname>
<given-names>Gou Young</given-names>
</name>
<xref ref-type="aff" rid="JCI75392">1</xref>
</contrib>
</contrib-group>
<aff id="JCI75392"><label>1</label>
National Research Laboratory of Vascular Biology and Stem Cells, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.<label>2</label>
Department of Surgery, Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.<label>3</label>
Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.<label>4</label>
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.<label>5</label>
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.<label>6</label>
Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, Department of Pathology, Haartman Institute and Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.</aff>
<author-notes><corresp>Address correspondence to: Gou Young Koh, Graduate School of Medical Science and
Engineering, KAIST, 373-1, Guseong-dong, Daejeon, 305-701, Korea. Phone: 82.42.350.2638;
E-mail: <email>gykoh@kaist.ac.kr</email>
. Or to: Young Kwon Hong, Departments of Surgery
and of Biochemistry & Molecular Biology, Keck School of Medicine, University of
Southern California, 1450 Biggy St., Los Angeles, California 90033, USA. Phone:
323.442.7825; E-mail: <email>young.hong@usc.edu</email>
.</corresp>
</author-notes>
<pub-date pub-type="epub"><day>25</day>
<month>7</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="ppub"><day>2</day>
<month>9</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>25</day>
<month>7</month>
<year>2014</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
. </pmc-comment>
<volume>124</volume>
<issue>9</issue>
<fpage>3960</fpage>
<lpage>3974</lpage>
<history><date date-type="received"><day>27</day>
<month>1</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>30</day>
<month>5</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2014, American Society for Clinical
Investigation</copyright-statement>
<copyright-year>2014</copyright-year>
<copyright-holder>American Society for Clinical Investigation</copyright-holder>
</permissions>
<abstract><p>Schlemm’s canal (SC) is a specialized vascular structure in the eye that functions
to drain aqueous humor from the intraocular chamber into systemic circulation. Dysfunction
of SC has been proposed to underlie increased aqueous humor outflow (AHO) resistance,
which leads to elevated ocular pressure, a factor for glaucoma development in humans.
Here, using lymphatic and blood vasculature reporter mice, we determined that SC, which
originates from blood vessels during the postnatal period, acquires lymphatic identity
through upregulation of prospero homeobox protein 1 (PROX1), the master regulator of
lymphatic development. SC expressed lymphatic valve markers FOXC2 and integrin
α<sub>9</sub>
and exhibited continuous vascular endothelial–cadherin
(VE-cadherin) junctions and basement membrane, similar to collecting lymphatics. SC
notably lacked luminal valves and expression of the lymphatic endothelial cell markers
podoplanin and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1). Using an
ocular puncture model, we determined that reduced AHO altered the fate of SC both during
development and under pathologic conditions; however, alteration of VEGF-C/VEGFR3
signaling did not modulate SC integrity and identity. Intriguingly, PROX1 expression
levels linearly correlated with SC functionality. For example, PROX1 expression was
reduced or undetectable under pathogenic conditions and in deteriorated SCs. Collectively,
our data indicate that PROX1 is an accurate and reliable biosensor of SC integrity and
identity.</p>
</abstract>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Corée du Sud</li>
<li>Finlande</li>
<li>Japon</li>
<li>Suède</li>
<li>États-Unis</li>
</country>
<region><li>Californie</li>
<li>East Middle Sweden</li>
<li>Svealand</li>
<li>Uusimaa</li>
</region>
<settlement><li>Helsinki</li>
<li>Los Angeles</li>
<li>Uppsala</li>
</settlement>
<orgName><li>Université d'Helsinki</li>
<li>Université d'Uppsala</li>
<li>Université de Californie du Sud</li>
</orgName>
</list>
<tree><country name="Corée du Sud"><noRegion><name sortKey="Park, Dae Young" sort="Park, Dae Young" uniqKey="Park D" first="Dae-Young" last="Park">Dae-Young Park</name>
</noRegion>
<name sortKey="Hong, Ki Yong" sort="Hong, Ki Yong" uniqKey="Hong K" first="Ki Yong" last="Hong">Ki Yong Hong</name>
<name sortKey="Hwang, Yoonha" sort="Hwang, Yoonha" uniqKey="Hwang Y" first="Yoonha" last="Hwang">Yoonha Hwang</name>
<name sortKey="Kim, Pilhan" sort="Kim, Pilhan" uniqKey="Kim P" first="Pilhan" last="Kim">Pilhan Kim</name>
<name sortKey="Koh, Gou Young" sort="Koh, Gou Young" uniqKey="Koh G" first="Gou Young" last="Koh">Gou Young Koh</name>
<name sortKey="Lee, Junyeop" sort="Lee, Junyeop" uniqKey="Lee J" first="Junyeop" last="Lee">Junyeop Lee</name>
<name sortKey="Park, Intae" sort="Park, Intae" uniqKey="Park I" first="Intae" last="Park">Intae Park</name>
<name sortKey="Song, Sukhyun" sort="Song, Sukhyun" uniqKey="Song S" first="Sukhyun" last="Song">Sukhyun Song</name>
</country>
<country name="États-Unis"><region name="Californie"><name sortKey="Choi, Dongwon" sort="Choi, Dongwon" uniqKey="Choi D" first="Dongwon" last="Choi">Dongwon Choi</name>
</region>
<name sortKey="Hong, Young Kwon" sort="Hong, Young Kwon" uniqKey="Hong Y" first="Young-Kwon" last="Hong">Young-Kwon Hong</name>
<name sortKey="Lee, Sunju" sort="Lee, Sunju" uniqKey="Lee S" first="Sunju" last="Lee">Sunju Lee</name>
</country>
<country name="Japon"><noRegion><name sortKey="Nakaoka, Yoshikazu" sort="Nakaoka, Yoshikazu" uniqKey="Nakaoka Y" first="Yoshikazu" last="Nakaoka">Yoshikazu Nakaoka</name>
</noRegion>
</country>
<country name="Suède"><region name="Svealand"><name sortKey="Makinen, Taija" sort="Makinen, Taija" uniqKey="Makinen T" first="Taija" last="Makinen">Taija Makinen</name>
</region>
</country>
<country name="Finlande"><region name="Uusimaa"><name sortKey="Alitalo, Kari" sort="Alitalo, Kari" uniqKey="Alitalo K" first="Kari" last="Alitalo">Kari Alitalo</name>
</region>
</country>
</tree>
</affiliations>
</record>
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