Abstract
Urinary tract morphogenesis requires subdivision of the ureteric bud (UB) into the intra-renal collecting system and the extra-renal ureter, by responding to signals in its surrounding mesenchyme. BMP4 is a mesenchymal regulator promoting ureter development, while GREM1 is necessary to negatively regulate BMP4 activity to induce UB branching. However, the mechanisms that regulate the GREM1-BMP4 signaling are unknown. Previous studies have shown that Six1-deficient mice lack kidneys, but form ureters. Here, we show that the tip cells of Six1(-/-) UB fail to form an ampulla for branching. Instead, the UB elongates within Tbx18- and Bmp4-expressing mesenchyme. We find that the expression of Grem1 in the metanephric mesenchyme (MM) is Six1-dependent. Treatment of Six1(-/-) kidney rudiments with GREM1 protein restores ampulla formation and branching morphogenesis. Furthermore, we demonstrate that genetic reduction of BMP4 levels in Six1(-/-) (Six1(-/-); Bmp4(+/-)) embryos restores urinary tract morphogenesis and kidney formation. This study uncovers an essential function for Six1 in the MM as an upstream regulator of Grem1 in initiating branching morphogenesis.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Bone Morphogenetic Protein 4 / metabolism
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Embryo, Mammalian / cytology
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Embryo, Mammalian / drug effects
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Embryo, Mammalian / metabolism
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Gene Dosage / drug effects
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Gene Expression Regulation, Developmental* / drug effects
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Gene Silencing / drug effects
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Glial Cell Line-Derived Neurotrophic Factor / metabolism
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Homeodomain Proteins / metabolism*
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Intercellular Signaling Peptides and Proteins / genetics*
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Intercellular Signaling Peptides and Proteins / metabolism
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Kidney / embryology
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Kidney / metabolism
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Mesoderm / cytology
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Mesoderm / drug effects
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Mesoderm / embryology*
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Mesoderm / metabolism
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Mice
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Morphogenesis* / drug effects
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Organogenesis / drug effects
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Recombinant Proteins / pharmacology
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T-Box Domain Proteins / metabolism
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Up-Regulation / drug effects
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Ureter / cytology
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Ureter / drug effects
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Ureter / embryology
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Ureter / metabolism
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Wnt Proteins / metabolism
Substances
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Bmp4 protein, mouse
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Bone Morphogenetic Protein 4
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Glial Cell Line-Derived Neurotrophic Factor
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Grem1 protein, mouse
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Homeodomain Proteins
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Intercellular Signaling Peptides and Proteins
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Recombinant Proteins
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Six1 protein, mouse
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T-Box Domain Proteins
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Tbx18 protein, mouse
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Wnt Proteins
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Wnt11 protein, mouse