Lmx1b and FoxC Combinatorially Regulate Podocin Expression in Podocytes
Identifieur interne : 002937 ( Main/Exploration ); précédent : 002936; suivant : 002938Lmx1b and FoxC Combinatorially Regulate Podocin Expression in Podocytes
Auteurs : Bing He ; Lwaki Ebarasi [Suède] ; Zhe Zhao [Royaume-Uni] ; Jing Guo ; Juha R. M. Ojala ; Kjell Hultenby [Suède] ; Sarah De Val [Royaume-Uni] ; Christer Betsholtz [Suède] ; Karl Tryggvason [Singapour]Source :
- Journal of the American Society of Nephrology : JASN [ 1046-6673 ] ; 2014.
Abstract
Podocin is a key protein of the kidney podocyte slit diaphragm protein complex, an important part of the glomerular filtration barrier. Mutations in the human podocin gene
Url:
DOI: 10.1681/ASN.2012080823
PubMed: 24854274
PubMed Central: 4243338
Affiliations:
- Royaume-Uni, Singapour, Suède
- Angleterre, East Middle Sweden, Oxfordshire, Svealand
- Oxford, Stockholm, Uppsala
- Université d'Uppsala
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Le document en format XML
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<front><div type="abstract" xml:lang="en"><p>Podocin is a key protein of the kidney podocyte slit diaphragm protein complex, an important part of the glomerular filtration barrier. Mutations in the human podocin gene <italic>NPHS2</italic>
cause familial or sporadic forms of renal disease owing to the disruption of filtration barrier integrity. The exclusive expression of <italic>NPHS2</italic>
in podocytes reflects its unique function and raises interesting questions about its transcriptional regulation. Here, we further define a 2.5-kb zebrafish <italic>nphs2</italic>
promoter fragment previously described and identify a 49-bp podocyte-specific transcriptional enhancer using Tol2-mediated G<sub>0</sub>
transgenesis in zebrafish. Within this enhancer, we identified a cis-acting element composed of two adjacent DNA-binding sites (FLAT-E and forkhead) bound by transcription factors Lmx1b and FoxC. In zebrafish, double knockdown of Lmx1b and FoxC orthologs using morpholino doses that caused no or minimal phenotypic changes upon individual knockdown completely disrupted podocyte development in 40% of injected embryos. Co-overexpression of the two genes potently induced endogenous <italic>nphs2</italic>
expression in zebrafish podocytes. We found that the <italic>NPHS2</italic>
promoter also contains a cis-acting Lmx1b-FoxC motif that binds LMX1B and FoxC2. Furthermore, a genome-wide search identified several genes that carry the Lmx1b-FoxC motif in their promoter regions. Among these candidates, motif-driven podocyte enhancer activity of <italic>CCNC</italic>
and <italic>MEIS2</italic>
was functionally analyzed <italic>in vivo</italic>
. Our results show that podocyte expression of some genes is combinatorially regulated by two transcription factors interacting synergistically with a common enhancer. This finding provides insights into transcriptional mechanisms required for normal and pathologic podocyte functions.</p>
</div>
</front>
</TEI>
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<li>Suède</li>
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<li>Svealand</li>
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<name sortKey="He, Bing" sort="He, Bing" uniqKey="He B" first="Bing" last="He">Bing He</name>
<name sortKey="Ojala, Juha R M" sort="Ojala, Juha R M" uniqKey="Ojala J" first="Juha R. M." last="Ojala">Juha R. M. Ojala</name>
</noCountry>
<country name="Suède"><region name="Svealand"><name sortKey="Ebarasi, Lwaki" sort="Ebarasi, Lwaki" uniqKey="Ebarasi L" first="Lwaki" last="Ebarasi">Lwaki Ebarasi</name>
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<name sortKey="Betsholtz, Christer" sort="Betsholtz, Christer" uniqKey="Betsholtz C" first="Christer" last="Betsholtz">Christer Betsholtz</name>
<name sortKey="Hultenby, Kjell" sort="Hultenby, Kjell" uniqKey="Hultenby K" first="Kjell" last="Hultenby">Kjell Hultenby</name>
</country>
<country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Zhao, Zhe" sort="Zhao, Zhe" uniqKey="Zhao Z" first="Zhe" last="Zhao">Zhe Zhao</name>
</region>
<name sortKey="De Val, Sarah" sort="De Val, Sarah" uniqKey="De Val S" first="Sarah" last="De Val">Sarah De Val</name>
</country>
<country name="Singapour"><noRegion><name sortKey="Tryggvason, Karl" sort="Tryggvason, Karl" uniqKey="Tryggvason K" first="Karl" last="Tryggvason">Karl Tryggvason</name>
</noRegion>
</country>
</tree>
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