title: A secreted BMP antagonist, Cer1, fine tunes the spatial organization of the ureteric bud tree during mouse kidney development.
abstract: 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.
authors: Laboratory 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.
authors: Lijun
authors: L
authors: Chi
authors: Ulla
authors: U
authors: Saarela
authors: Antti
authors: A
authors: Railo
authors: Renata
authors: R
authors: Prunskaite-Hyyryläinen
authors: Ilya
authors: I
authors: Skovorodkin
authors: Shelagh
authors: S
authors: Anthony
authors: Kenjiro
authors: K
authors: Katsu
authors: Yu
authors: Y
authors: Liu
authors: Jingdong
authors: J
authors: Shan
authors: Ana Marisa
authors: AM
authors: Salgueiro
authors: José António
authors: JA
authors: Belo
authors: Jamie
authors: J
authors: Davies
authors: Yuji
authors: Y
authors: Yokouchi
authors: Seppo J
authors: SJ
authors: Vainio
mesh_terms: D000818:Animals; D015153:Blotting, Western; D055415:Bone Morphogenetic Protein 4 / Q000037:antagonists & inhibitors*; D016207:Cytokines; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D007668:Kidney / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis; D011506:Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000502:physiology; D015398:Signal Transduction; D020349:Surface Plasmon Resonance; D014513:Ureter / Q000196:embryology* / Q000378:metabolism*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; C110586:Cer1 protein, mouse; D016207:Cytokines; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D051153:Wnt Proteins; C508957:Wnt11 protein, mouse