University of Oulu

Chi L, Saarela U, Railo A, Prunskaite-Hyyryläinen R, Skovorodkin I, Anthony S, et al. (2011) A Secreted BMP Antagonist, Cer1, Fine Tunes the Spatial Organization of the Ureteric Bud Tree during Mouse Kidney Development. PLoS ONE 6(11): e27676.

A secreted BMP antagonist, Cer1, fine tunes the spatial organization of the ureteric bud tree during mouse kidney development

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Author: Chi, Lijun1; Saarela, Ulla1; Railo, Antti1;
Organizations: 1Laboratory of Developmental Biology, Department of Medical Biochemistry and Molecular Biology, Center for Cell Matrix Research, Institute of Biomedicine Oulu, Biocenter Oulu, University of Oulu, Oulu, Finland
2Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom
3Division of Pattern Formation, Department of Organogenesis, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
4Texas A&M Health Science Center, Center for Development and Diseases, Institute of Biosciences and Technology, Houston, Texas, United States of America
5Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, Regenerative Medicine Program, Algarve, Portugal
6IBB-Institute for Biotechnology and Bioengineering, Centro de Biomedicina Molecular e Estrutural, Universidade do Algarve, Faro, Portugal
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.9 MB)
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Language: English
Published: Public Library of Science, 2011
Publish Date: 2020-05-11


The epithelial ureteric bud is critical for mammalian kidney development as it generates the ureter and the collecting duct system that induces nephrogenesis in dicrete locations in the kidney mesenchyme during its emergence. We show that a secreted Bmp antagonist Cerberus homologue (Cer1) fine tunes the organization of the ureteric tree during organogenesis in the mouse embryo. Both enhanced ureteric expression of Cer1 and Cer1 knock out enlarge kidney size, and these changes are associated with an altered three-dimensional structure of the ureteric tree as revealed by optical projection tomography. Enhanced Cer1 expression changes the ureteric bud branching programme so that more trifid and lateral branches rather than bifid ones develop, as seen in time-lapse organ culture. These changes may be the reasons for the modified spatial arrangement of the ureteric tree in the kidneys of Cer1+ embryos. Cer1 gain of function is associated with moderately elevated expression of Gdnf and Wnt11, which is also induced in the case of Cer1 deficiency, where Bmp4 expression is reduced, indicating the dependence of Bmp expression on Cer1. Cer1 binds at least Bmp2/4 and antagonizes Bmp signalling in cell culture. In line with this, supplementation of Bmp4 restored the ureteric bud tip number, which was reduced by Cer1+ to bring it closer to the normal, consistent with models suggesting that Bmp signalling inhibits ureteric bud development. Genetic reduction of Wnt11 inhibited the Cer1-stimulated kidney development, but Cer1 did not influence Wnt11 signalling in cell culture, although it did inhibit the Wnt3a-induced canonical Top Flash reporter to some extent. We conclude that Cer1 fine tunes the spatial organization of the ureteric tree by coordinating the activities of the growth-promoting ureteric bud signals Gndf and Wnt11 via Bmp-mediated antagonism and to some degree via the canonical Wnt signalling involved in branching.

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Series: PLoS one
ISSN: 1932-6203
ISSN-E: 1932-6203
ISSN-L: 1932-6203
Volume: 6
Issue: 11
Article number: e27676
DOI: 10.1371/journal.pone.0027676
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: The project was supported financially by grants from the Academy of Finland Centre of Excellence Programme 2012-2017, the Sigrid Jusélius Foundation, the Finnish Cancer Organizations, the UK Medical Research Council, the European Union (EuReGene, LSHG-CT-2004-005085; HEALTH-F5-2008-223007 STAR-T REK and F.C.T. and IBB/CBME, LA to J.A. Belo. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Copyright information: © 2011 Chi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.