uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Lmx1b and FoxC Combinatorially Regulate Podocin Expression in Podocytes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
Show others and affiliations
2014 (English)In: Journal of the American Society of Nephrology, ISSN 1046-6673, Vol. 25, no 12, 2764-2777 p.Article in journal (Refereed) Published
Abstract [en]

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 NPHS2 cause familial or sporadic forms of renal disease owing to the disruption of filtration barrier integrity. The exclusive expression of NPHS2 in podocytes reflects its unique function and raises interesting questions about its transcriptional regulation. Here, we further define a 2.5-kb zebrafish nphs2 promoter fragment previously described and identify a 49-bp podocyte-specific transcriptional enhancer using Tol2-mediated G(0) 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 Lnnx1b 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 nphs2 expression in zebrafish podocytes. We found that the NPHS2 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 CCNC and MEIS2 was functionally analyzed in vivo. 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.

Place, publisher, year, edition, pages
2014. Vol. 25, no 12, 2764-2777 p.
National Category
Urology and Nephrology
URN: urn:nbn:se:uu:diva-240216DOI: 10.1681/ASN.2012080823ISI: 000345607500012PubMedID: 24854274OAI: oai:DiVA.org:uu-240216DiVA: diva2:776413
Available from: 2015-01-07 Created: 2015-01-06 Last updated: 2015-01-07Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Ebarasi, LwakiBetsholtz, Christer
By organisation
Cancer and Vascular Biology
In the same journal
Journal of the American Society of Nephrology
Urology and Nephrology

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 211 hits
ReferencesLink to record
Permanent link

Direct link