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First published online 23 May 2007
doi: 10.1242/dev.02861

This Article Figures Only Full Text Full Text (PDF) Supplementary Material All Versions of this Article: dev.02861v1 134/13/2397    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in Development Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Michos, O. Articles by Zeller, R. Search for Related Content PubMed PubMed Citation Articles by Michos, O. Articles by Zeller, R. Social Bookmarking                         What's this?

Reduction of BMP4 activity by gremlin 1 enables ureteric bud outgrowth and GDNF/WNT11 feedback signalling during kidney branching morphogenesis

Odyssé Michos^1,*,, Alexandre Gonçalves^1,*, Javier Lopez-Rios¹, Eva Tiecke¹, Florence Naillat², Konstantin Beier³, Antonella Galli¹, Seppo Vainio² and Rolf Zeller^1,

¹ Developmental Genetics, DKBW Centre for Biomedicine, University of Basel Medical Faculty, Mattenstrasse 28, CH-4058 Basel, Switzerland.
² Department of Medical Biochemistry and Molecular Biology, Biocenter Oulu, Laboratory of Developmental Biology, Aapistie 5A, PO Box 5000, University of Oulu, F-90570 Oulu, Finland.
³ Department of Histology, Anatomy Institute, Pestalozzistrasse 20, CH-4056 Basel, Switzerland.

Author for correspondence (e-mail: Rolf.Zeller{at}unibas.ch)

Accepted 5 April 2007

Antagonists act to restrict and negatively modulate the activity of secreted signals during progression of embryogenesis. In mouse embryos lacking the extra-cellular BMP antagonist gremlin 1 (Grem1), metanephric development is disrupted at the stage of initiating ureteric bud outgrowth. Treatment of mutant kidney rudiments in culture with recombinant gremlin 1 protein induces additional epithelial buds and restores outgrowth and branching. All epithelial buds express Wnt11, and Gdnf is significantly upregulated in the surrounding mesenchyme, indicating that epithelial-mesenchymal (e-m) feedback signalling is restored. In the wild type, Bmp4 is expressed by the mesenchyme enveloping the Wolffian duct and ureteric bud and Grem1 is upregulated in the mesenchyme around the nascent ureteric bud prior to initiation of its outgrowth. In agreement, BMP activity is reduced locally as revealed by lower levels of nuclear pSMAD protein in the mesenchyme. By contrast, in Grem1-deficient kidney rudiments, pSMAD proteins are detected in many cell nuclei in the metanephric mesenchyme, indicative of excessive BMP signal transduction. Indeed, genetic lowering of BMP4 levels in Grem1-deficient mouse embryos completely restores ureteric bud outgrowth and branching morphogenesis. The reduction of BMP4 levels in Grem1 mutant embryos enables normal progression of renal development and restores adult kidney morphology and functions. This study establishes that initiation of metanephric kidney development requires the reduction of BMP4 activity by the antagonist gremlin 1 in the mesenchyme, which in turn enables ureteric bud outgrowth and establishment of autoregulatory GDNF/WNT11 feedback signalling.

Key words: Antagonist, BMP, gremlin 1, Kidney, Mouse, Signalling

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