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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">FGF-regulated BMP signaling is required for eyelid closure and to specify
conjunctival epithelial cell fate</title><author><name sortKey="Huang, Jie" sort="Huang, Jie" uniqKey="Huang J" first="Jie" last="Huang">Jie Huang</name><affiliation><nlm:aff id="aff1"> Department of Ophthalmology and Visual Sciences, Washington University, St Louis, MO 63130, USA.</nlm:aff></affiliation></author><author><name sortKey="Dattilo, Lisa K" sort="Dattilo, Lisa K" uniqKey="Dattilo L" first="Lisa K." last="Dattilo">Lisa K. Dattilo</name><affiliation><nlm:aff id="aff1"> Department of Ophthalmology and Visual Sciences, Washington University, St Louis, MO 63130, USA.</nlm:aff></affiliation></author><author><name sortKey="Rajagopal, Ramya" sort="Rajagopal, Ramya" uniqKey="Rajagopal R" first="Ramya" last="Rajagopal">Ramya Rajagopal</name><affiliation><nlm:aff id="aff1"> Department of Ophthalmology and Visual Sciences, Washington University, St Louis, MO 63130, USA.</nlm:aff></affiliation></author><author><name sortKey="Liu, Ying" sort="Liu, Ying" uniqKey="Liu Y" first="Ying" last="Liu">Ying Liu</name><affiliation><nlm:aff id="aff1"> Department of Ophthalmology and Visual Sciences, Washington University, St Louis, MO 63130, USA.</nlm:aff></affiliation></author><author><name sortKey="Kaartinen, Vesa" sort="Kaartinen, Vesa" uniqKey="Kaartinen V" first="Vesa" last="Kaartinen">Vesa Kaartinen</name><affiliation><nlm:aff id="aff3"> Developmental Biology Program, Childrens Hospital Los Angeles, Departments of Pathology and Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.</nlm:aff></affiliation></author><author><name sortKey="Mishina, Yuji" sort="Mishina, Yuji" uniqKey="Mishina Y" first="Yuji" last="Mishina">Yuji Mishina</name><affiliation><nlm:aff id="aff4"> Molecular Developmental Biology Group, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.</nlm:aff></affiliation></author><author><name sortKey="Deng, Chu Xia" sort="Deng, Chu Xia" uniqKey="Deng C" first="Chu-Xia" last="Deng">Chu-Xia Deng</name><affiliation><nlm:aff id="aff5"> Genetics of Development and Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.</nlm:aff></affiliation></author><author><name sortKey="Umans, Lieve" sort="Umans, Lieve" uniqKey="Umans L" first="Lieve" last="Umans">Lieve Umans</name><affiliation><nlm:aff id="aff6"> Laboratory Molecular Biology (Celgen), Department for Molecular and Developmental Genetics, VIB, B-3000 Leuven, Belgium.</nlm:aff></affiliation><affiliation><nlm:aff id="aff7"> Laboratory Molecular Biology (Celgen), Center for Human Genetics, KU Leuven, B-3000 Leuven, Belgium.</nlm:aff></affiliation></author><author><name sortKey="Zwijsen, An" sort="Zwijsen, An" uniqKey="Zwijsen A" first="An" last="Zwijsen">An Zwijsen</name><affiliation><nlm:aff id="aff6"> Laboratory Molecular Biology (Celgen), Department for Molecular and Developmental Genetics, VIB, B-3000 Leuven, Belgium.</nlm:aff></affiliation><affiliation><nlm:aff id="aff7"> Laboratory Molecular Biology (Celgen), Center for Human Genetics, KU Leuven, B-3000 Leuven, Belgium.</nlm:aff></affiliation></author><author><name sortKey="Roberts, Anita B" sort="Roberts, Anita B" uniqKey="Roberts A" first="Anita B." last="Roberts">Anita B. Roberts</name><affiliation><nlm:aff id="aff8"> Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.</nlm:aff></affiliation></author><author><name sortKey="Beebe, David C" sort="Beebe, David C" uniqKey="Beebe D" first="David C." last="Beebe">David C. Beebe</name><affiliation><nlm:aff id="aff1"> Department of Ophthalmology and Visual Sciences, Washington University, St Louis, MO 63130, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="aff2"> Department of Cell Biology and Physiology, Washington University, St Louis, MO 63130, USA.</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">19369394</idno><idno type="pmc">2673764</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673764</idno><idno type="RBID">PMC:2673764</idno><idno type="doi">10.1242/dev.034082</idno><date when="2009">2009</date><idno type="wicri:Area/Pmc/Corpus">001750</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001750</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">FGF-regulated BMP signaling is required for eyelid closure and to specify
conjunctival epithelial cell fate</title><author><name sortKey="Huang, Jie" sort="Huang, Jie" uniqKey="Huang J" first="Jie" last="Huang">Jie Huang</name><affiliation><nlm:aff id="aff1"> Department of Ophthalmology and Visual Sciences, Washington University, St Louis, MO 63130, USA.</nlm:aff></affiliation></author><author><name sortKey="Dattilo, Lisa K" sort="Dattilo, Lisa K" uniqKey="Dattilo L" first="Lisa K." last="Dattilo">Lisa K. Dattilo</name><affiliation><nlm:aff id="aff1"> Department of Ophthalmology and Visual Sciences, Washington University, St Louis, MO 63130, USA.</nlm:aff></affiliation></author><author><name sortKey="Rajagopal, Ramya" sort="Rajagopal, Ramya" uniqKey="Rajagopal R" first="Ramya" last="Rajagopal">Ramya Rajagopal</name><affiliation><nlm:aff id="aff1"> Department of Ophthalmology and Visual Sciences, Washington University, St Louis, MO 63130, USA.</nlm:aff></affiliation></author><author><name sortKey="Liu, Ying" sort="Liu, Ying" uniqKey="Liu Y" first="Ying" last="Liu">Ying Liu</name><affiliation><nlm:aff id="aff1"> Department of Ophthalmology and Visual Sciences, Washington University, St Louis, MO 63130, USA.</nlm:aff></affiliation></author><author><name sortKey="Kaartinen, Vesa" sort="Kaartinen, Vesa" uniqKey="Kaartinen V" first="Vesa" last="Kaartinen">Vesa Kaartinen</name><affiliation><nlm:aff id="aff3"> Developmental Biology Program, Childrens Hospital Los Angeles, Departments of Pathology and Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.</nlm:aff></affiliation></author><author><name sortKey="Mishina, Yuji" sort="Mishina, Yuji" uniqKey="Mishina Y" first="Yuji" last="Mishina">Yuji Mishina</name><affiliation><nlm:aff id="aff4"> Molecular Developmental Biology Group, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.</nlm:aff></affiliation></author><author><name sortKey="Deng, Chu Xia" sort="Deng, Chu Xia" uniqKey="Deng C" first="Chu-Xia" last="Deng">Chu-Xia Deng</name><affiliation><nlm:aff id="aff5"> Genetics of Development and Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.</nlm:aff></affiliation></author><author><name sortKey="Umans, Lieve" sort="Umans, Lieve" uniqKey="Umans L" first="Lieve" last="Umans">Lieve Umans</name><affiliation><nlm:aff id="aff6"> Laboratory Molecular Biology (Celgen), Department for Molecular and Developmental Genetics, VIB, B-3000 Leuven, Belgium.</nlm:aff></affiliation><affiliation><nlm:aff id="aff7"> Laboratory Molecular Biology (Celgen), Center for Human Genetics, KU Leuven, B-3000 Leuven, Belgium.</nlm:aff></affiliation></author><author><name sortKey="Zwijsen, An" sort="Zwijsen, An" uniqKey="Zwijsen A" first="An" last="Zwijsen">An Zwijsen</name><affiliation><nlm:aff id="aff6"> Laboratory Molecular Biology (Celgen), Department for Molecular and Developmental Genetics, VIB, B-3000 Leuven, Belgium.</nlm:aff></affiliation><affiliation><nlm:aff id="aff7"> Laboratory Molecular Biology (Celgen), Center for Human Genetics, KU Leuven, B-3000 Leuven, Belgium.</nlm:aff></affiliation></author><author><name sortKey="Roberts, Anita B" sort="Roberts, Anita B" uniqKey="Roberts A" first="Anita B." last="Roberts">Anita B. Roberts</name><affiliation><nlm:aff id="aff8"> Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.</nlm:aff></affiliation></author><author><name sortKey="Beebe, David C" sort="Beebe, David C" uniqKey="Beebe D" first="David C." last="Beebe">David C. Beebe</name><affiliation><nlm:aff id="aff1"> Department of Ophthalmology and Visual Sciences, Washington University, St Louis, MO 63130, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="aff2"> Department of Cell Biology and Physiology, Washington University, St Louis, MO 63130, USA.</nlm:aff></affiliation></author></analytic><series><title level="j">Development (Cambridge, England)</title><idno type="ISSN">0950-1991</idno><idno type="eISSN">1477-9129</idno><imprint><date when="2009">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Summary</title><p>There are conflicting reports about whether BMP signaling is required for
eyelid closure during fetal development. This question was addressed using
mice deficient in BMP or TGFβ signaling in prospective eyelid and
conjunctival epithelial cells. Genes encoding two type I BMP receptors, the
type II TGFβ receptor, two BMP- or two TGFβ-activated R-Smads or the
co-Smad Smad4 were deleted from the ocular surface ectoderm using Cre
recombinase. Only mice with deletion of components of the BMP pathway had an
`eyelid open at birth' phenotype. Mice lacking <italic>Fgf10</italic> or
<italic>Fgfr2</italic> also have open eyelids at birth. To better understand the
pathways that regulate BMP expression and function during eyelid development,
we localized BMPs and BMP signaling intermediates in <italic>Fgfr2</italic> and
<italic>Smad4</italic> conditional knockout (CKO) mice. We found that Fgfr2 was
required for the expression of <italic>Bmp4</italic>, the normal distribution of Shh
signaling and for preserving the differentiation of the conjunctival
epithelium. FGF signaling also promoted the expression of the Wnt antagonist
Sfrp1 and suppressed Wnt signaling in the prospective eyelid epithelial cells,
independently of BMP function. Transcripts encoding Foxc1 and Foxc2, which
were previously shown to be necessary for eyelid closure, were not detectable
in <italic>Smad4<sup>CKO</sup></italic> animals. c-Jun, another key regulator of
eyelid closure, was present and phosphorylated in eyelid periderm cells at the
time of fusion, but failed to translocate to the nucleus in the absence of BMP
function. <italic>Smad4<sup>CKO</sup></italic> mice also showed premature
differentiation of the conjunctival epithelium, conjunctival hyperplasia and
the acquisition of epidermal characteristics, including formation of an
ectopic row of hair follicles in place of the Meibomian glands. A second row
of eyelashes is a feature of human lymphedema-distichiasis syndrome, which is
associated with mutations in FOXC2.</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">Development</journal-id><journal-id journal-id-type="publisher-id">develop</journal-id><journal-title>Development (Cambridge, England)</journal-title><issn pub-type="ppub">0950-1991</issn><issn pub-type="epub">1477-9129</issn><publisher><publisher-name>Company of Biologists</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">19369394</article-id><article-id pub-id-type="pmc">2673764</article-id><article-id pub-id-type="publisher-id">1741</article-id><article-id pub-id-type="doi">10.1242/dev.034082</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Articles</subject></subj-group></article-categories><title-group><article-title>FGF-regulated BMP signaling is required for eyelid closure and to specify
conjunctival epithelial cell fate</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Huang</surname><given-names>Jie</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Dattilo</surname><given-names>Lisa K.</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Rajagopal</surname><given-names>Ramya</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Ying</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kaartinen</surname><given-names>Vesa</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Mishina</surname><given-names>Yuji</given-names></name><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Deng</surname><given-names>Chu-Xia</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Umans</surname><given-names>Lieve</given-names></name><xref ref-type="aff" rid="aff6">6</xref><xref ref-type="aff" rid="aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Zwijsen</surname><given-names>An</given-names></name><xref ref-type="aff" rid="aff6">6</xref><xref ref-type="aff" rid="aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Roberts</surname><given-names>Anita B.</given-names></name><xref ref-type="aff" rid="aff8">8</xref></contrib><contrib contrib-type="author"><name><surname>Beebe</surname><given-names>David C.</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff id="aff1"><label>1</label> Department of Ophthalmology and Visual Sciences, Washington University, St Louis, MO 63130, USA.</aff><aff id="aff2"><label>2</label> Department of Cell Biology and Physiology, Washington University, St Louis, MO 63130, USA.</aff><aff id="aff3"><label>3</label> Developmental Biology Program, Childrens Hospital Los Angeles, Departments of Pathology and Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.</aff><aff id="aff4"><label>4</label> Molecular Developmental Biology Group, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.</aff><aff id="aff5"><label>5</label> Genetics of Development and Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.</aff><aff id="aff6"><label>6</label> Laboratory Molecular Biology (Celgen), Department for Molecular and Developmental Genetics, VIB, B-3000 Leuven, Belgium.</aff><aff id="aff7"><label>7</label> Laboratory Molecular Biology (Celgen), Center for Human Genetics, KU Leuven, B-3000 Leuven, Belgium.</aff><aff id="aff8"><label>8</label> Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.</aff><author-notes><fn id="cor1"><label>*</label><p>Author for correspondence (e-mail:
<email>Beebe@vision.wustl.edu</email>)
</p></fn></author-notes><pub-date pub-type="ppub"><day>15</day><month>5</month><year>2009</year></pub-date><pub-date pub-type="epub"><day>15</day><month>4</month><year>2009</year></pub-date><pub-date pub-type="pmc-release"><day>15</day><month>5</month><year>2010</year></pub-date><pmc-comment> PMC Release delay is 12 months and 0 days and was based on the copyright element. </pmc-comment>
<volume>136</volume><issue>10</issue><fpage>1741</fpage><lpage>1750</lpage><history><date date-type="accepted"><day>9</day><month>3</month><year>2009</year></date></history><permissions></permissions><self-uri xlink:title="pdf" xlink:href="1741.pdf"></self-uri><abstract><title>Summary</title><p>There are conflicting reports about whether BMP signaling is required for
eyelid closure during fetal development. This question was addressed using
mice deficient in BMP or TGFβ signaling in prospective eyelid and
conjunctival epithelial cells. Genes encoding two type I BMP receptors, the
type II TGFβ receptor, two BMP- or two TGFβ-activated R-Smads or the
co-Smad Smad4 were deleted from the ocular surface ectoderm using Cre
recombinase. Only mice with deletion of components of the BMP pathway had an
`eyelid open at birth' phenotype. Mice lacking <italic>Fgf10</italic> or
<italic>Fgfr2</italic> also have open eyelids at birth. To better understand the
pathways that regulate BMP expression and function during eyelid development,
we localized BMPs and BMP signaling intermediates in <italic>Fgfr2</italic> and
<italic>Smad4</italic> conditional knockout (CKO) mice. We found that Fgfr2 was
required for the expression of <italic>Bmp4</italic>, the normal distribution of Shh
signaling and for preserving the differentiation of the conjunctival
epithelium. FGF signaling also promoted the expression of the Wnt antagonist
Sfrp1 and suppressed Wnt signaling in the prospective eyelid epithelial cells,
independently of BMP function. Transcripts encoding Foxc1 and Foxc2, which
were previously shown to be necessary for eyelid closure, were not detectable
in <italic>Smad4<sup>CKO</sup></italic> animals. c-Jun, another key regulator of
eyelid closure, was present and phosphorylated in eyelid periderm cells at the
time of fusion, but failed to translocate to the nucleus in the absence of BMP
function. <italic>Smad4<sup>CKO</sup></italic> mice also showed premature
differentiation of the conjunctival epithelium, conjunctival hyperplasia and
the acquisition of epidermal characteristics, including formation of an
ectopic row of hair follicles in place of the Meibomian glands. A second row
of eyelashes is a feature of human lymphedema-distichiasis syndrome, which is
associated with mutations in FOXC2.</p></abstract><kwd-group><kwd><bold>Eyelid closure</bold></kwd><kwd><bold>Conjunctival cell fate</bold></kwd><kwd><bold>c-Jun nuclear transport</bold></kwd><kwd><bold>BMP signaling</bold></kwd><kwd><bold>FGF signaling</bold></kwd><kwd><bold>Mouse</bold></kwd></kwd-group></article-meta><notes><fn-group><fn><p><bold>Supplementary material</bold></p></fn><fn><p>Supplementary material available online at
<ext-link ext-link-type="uri" xlink:href="http://dev.biologists.org/cgi/content/full/136/10/1741/DC1">http://dev.biologists.org/cgi/content/full/136/10/1741/DC1</ext-link></p></fn><fn><p>The authors are indebted to Drs Zhen Mahoney and Jeff Miner for generously
sharing reagents, for many suggestions on the technical aspects of this work
and for assistance in editing. Belinda McMahan and Jean Jones prepared the
histological sections and Dr Claudia Garcia provided guidance with the
<italic>Fgfr2</italic> conditional knockouts, which were generously provided by Dr
David Ornitz, Washington University, St Louis. The <italic>Psen1</italic> and
<italic>Psen2</italic> floxed and mutant mice were generously provided by Dr J. Shen,
Brigham and Women's Hospital, Boston, MA and Dr Raphael Kopan, Washington
University, St Louis. Drs Peter Gruss and Ruth Ashery-Padan generated and
provided the Le-Cre mice. Research was supported by
<grant-sponsor>NIH</grant-sponsor> grant
<grant-num>EY04853</grant-num> (D.C.B.) and
<grant-sponsor>NIH</grant-sponsor> Core Grant
<grant-num>P30 EY02687</grant-num> and an unrestricted grant from
<grant-sponsor>Research to Prevent Blindness to the Department of
Ophthalmology and Visual Sciences</grant-sponsor>. Deposited in PMC for
release after 12 months.</p></fn></fn-group></notes></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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