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Burghardt, T.* ; Kastner, J.* ; Suleiman, H.* ; Rivera-Milla, E.* ; Stepanova, N.* ; Lottaz, C.* ; Kubitza, M.* ; Böger, C.A.* ; Schmidt, S.* ; Gorski, M.* ; de Vries, U.* ; Schmidt, H.* ; Hertting, I.* ; Kopp, J.* ; Rascle, A.* ; Moser, M.* ; Heid, I.M. ; Warth, R.* ; Spang, R.* ; Wegener, J. ; Mierke, C.T.* ; Englert, C.* ; Witzgall, R.*

LMX1B is essential for the maintenance of differentiated podocytes in adult kidneys.

J. Am. Soc. Nephrol. 24, 1830-1848 (2013)
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Mutations of the LMX1B gene cause nail-patella syndrome, a rare autosomal-dominant disorder affecting the development of the limbs, eyes, brain, and kidneys. The characterization of conventional Lmx1b knockout mice has shown that LMX1B regulates the development of podocyte foot processes and slit diaphragms, but studies using podocyte-specific Lmx1b knockout mice have yielded conflicting results regarding the importance of LMX1B for maintaining podocyte structures. In order to address this question, we generated inducible podocyte-specific Lmx1b knockout mice. One week of Lmx1b inactivation in adult mice resulted in proteinuria with only minimal foot process effacement. Notably, expression levels of slit diaphragm and basement membrane proteins remained stable at this time point, and basement membrane charge properties also did not change, suggesting that alternative mechanisms mediate the development of proteinuria in these mice. Cell biological and biophysical experiments with primary podocytes isolated after 1 week of Lmx1b inactivation indicated dysregulation of actin cytoskeleton organization, and time-resolved DNA microarray analysis identified the genes encoding actin cytoskeleton-associated proteins, including Abra and Arl4c, as putative LMX1B targets. Chromatin immunoprecipitation experiments in conditionally immortalized human podocytes and gel shift assays showed that LMX1B recognizes AT-rich binding sites (FLAT elements) in the promoter regions of ABRA and ARL4C, and knockdown experiments in zebrafish support a model in which LMX1B and ABRA act in a common pathway during pronephros development. Our report establishes the importance of LMX1B in fully differentiated podocytes and argues that LMX1B is essential for the maintenance of an appropriately structured actin cytoskeleton in podocytes.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Nail-patella Syndrome; Focal Segmental Glomerulosclerosis; Transcription Factor; Actin Cytoskeleton; Gene-expression; Crucial Role; Mutant Mice; In-vivo; Protein; Nephrin
Language english
Publication Year 2013
HGF-reported in Year 2013
ISSN (print) / ISBN 1046-6673
e-ISSN 1533-3450
Journal Journal of the American Society of Nephrology
Quellenangaben Volume: 24, Issue: 11, Pages: 1830-1848 Article Number: , Supplement: ,
Publisher American Society of Nephrology
Reviewing status Peer reviewed
Institute(s) Institute of Genetic Epidemiology (IGE)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-504100-001
PubMed ID 23990680
DOI 10.1681/ASN.2012080788
WOS ID WOS:000329911300015
Scopus ID 84887102090
Erfassungsdatum 2013-11-19
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