title: Six1 regulates Grem1 expression in the metanephric mesenchyme to initiate branching morphogenesis.
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.
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of NYU, New York, NY 10029, USA.
authors.forename: Xuguang
authors.initials: X
authors.lastname: Nie
authors.forename: Jinshu
authors.initials: J
authors.lastname: Xu
authors.forename: Ahmed
authors.initials: A
authors.lastname: El-Hashash
authors.forename: Pin-Xian
authors.initials: PX
authors.lastname: Xu
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018628:Gene Dosage / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000196:embryology / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis / Q000187:drug effects; D038081:Organogenesis / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D020825:T-Box Domain Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014513:Ureter / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D016207:Cytokines
chemical_list: D055415:Bone Morphogenetic Protein 4; D051100:Glial Cell Line-Derived Neurotrophic Factor; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; D020825:T-Box Domain Proteins; D051153:Wnt Proteins; C525810:Bmp4 protein, mouse; C490947:Six1 protein, mouse; C420983:Tbx18 protein, mouse; C508957:Wnt11 protein, mouse; C113178:Grem1 protein, mouse; D016207:Cytokines