title: Fstl1 antagonizes BMP signaling and regulates ureter development.
abstract: Bone morphogenetic protein (BMP) signaling pathway plays important roles in urinary tract development although the detailed regulation of its activity in this process remains unclear. Here we report that follistatin-like 1 (Fstl1), encoding a secreted extracellular glycoprotein, is expressed in developing ureter and antagonizes BMP signaling activity. Mouse embryos carrying disrupted Fstl1 gene displayed prominent hydroureter arising from proximal segment and ureterovesical junction defects. These defects were associated with significant reduction in ureteric epithelial cell proliferation at E15.5 and E16.5 as well as absence of subepithelial ureteral mesenchymal cells in the urinary tract at E16.5 and E18.5. At the molecular level, increased BMP signaling was found in Fstl1 deficient ureters, indicated by elevated pSmad1/5/8 activity. In vitro study also indicated that Fstl1 can directly bind to ALK6 which is specifically expressed in ureteric epithelial cells in developing ureter. Furthermore, Sonic hedgehog (SHH) signaling, which is crucial for differentiation of ureteral subepithelial cell proliferation, was also impaired in Fstl1(-/-) ureter. Altogether, our data suggest that Fstl1 is essential in maintaining normal ureter development by antagonizing BMP signaling.
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
authors.forename: Jingyue
authors.initials: J
authors.lastname: Xu
authors.forename: Xin
authors.initials: X
authors.lastname: Qi
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Gong
authors.forename: Mingyan
authors.initials: M
authors.lastname: Yu
authors.forename: Fangxiong
authors.initials: F
authors.lastname: Zhang
authors.forename: Haibo
authors.initials: H
authors.lastname: Sha
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
mesh_terms: D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D038702:Follistatin-Related Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D014513:Ureter / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D014551:Urinary Tract / Q000166:cytology / Q000196:embryology / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D038702:Follistatin-Related Proteins; C448720:Fstl1 protein, mouse; D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I