| Dokumentenart: | Artikel | ||||||||||||||||||||||||||||||||||||
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| Titel eines Journals oder einer Zeitschrift: | Journal of the American Society of Nephrology : JASN | ||||||||||||||||||||||||||||||||||||
| Verlag: | American Society of Nephrology | ||||||||||||||||||||||||||||||||||||
| Band: | 24 | ||||||||||||||||||||||||||||||||||||
| Nummer des Zeitschriftenheftes oder des Kapitels: | 11 | ||||||||||||||||||||||||||||||||||||
| Seitenbereich: | S. 1830-1848 | ||||||||||||||||||||||||||||||||||||
| Datum: | November 2013 | ||||||||||||||||||||||||||||||||||||
| Institutionen: | Medizin > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) | ||||||||||||||||||||||||||||||||||||
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| Dewey-Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik > 500 Naturwissenschaften 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin | ||||||||||||||||||||||||||||||||||||
| Status: | Veröffentlicht | ||||||||||||||||||||||||||||||||||||
| Begutachtet: | Ja, diese Version wurde begutachtet | ||||||||||||||||||||||||||||||||||||
| An der Universität Regensburg entstanden: | Zum Teil | ||||||||||||||||||||||||||||||||||||
| Dokumenten-ID: | 30566 |
Zusammenfassung
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 ...
Zusammenfassung
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.
Metadaten zuletzt geändert: 29 Sep 2021 07:40
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