title: Antagonism of BMP4 signaling disrupts smooth muscle investment of the ureter and ureteropelvic junction.
abstract: OBJECTIVE
  Congenital ureteropelvic junction obstruction has been associated with aberrant ureteral smooth muscle organization. Recent evidence has shown that BMP4 may be involved in ureteral morphogenesis. We determined whether the disruption of BMP4 signaling results in abnormal smooth muscle investment of the ureter and ureteropelvic junction.
  
  
  METHODS
  We used a Cre mediated Bmp4 knockout system to conditionally excise the Bmp4 gene in developing mouse embryos. Kidney rudiments were isolated from embryos at varying gestational ages from WT and conditional knockout mice. Metanephric kidney explants were cultured in the presence or absence of the BMP antagonist Noggin. Agarose beads pre-incubated with Gremlin, another BMP antagonist, were used for localized disruption of BMP signaling. Frozen sections and whole metanephric explants were then analyzed by immunofluorescence.
  
  
  RESULTS
  Bmp4 gene excision resulted in a dose dependent loss of ureteral smooth muscle. Antagonism of BMP signaling inhibited ureteral smooth muscle investment in a dose dependent manner and was paralleled by a dose dependent decrease in the immediate downstream targets of BMP signaling, phosphorylated Smad1, 5 and 8. Localized antagonism of BMP resulted in the focal disruption of ureteral smooth muscle investment.
  
  
  CONCLUSIONS
  We report that decreased BMP signaling, whether by the loss of BMP4 in vivo or direct antagonism in vitro, results in a gradual reduction of the normal, well organized coat of smooth muscle surrounding the ureter. Our results also suggest that this occurs via a direct Smad dependent pathway. This raises the possibility that abnormalities in BMP4 signaling may have a role in the development of congenital ureteropelvic junction obstruction.
authors.affiliation: Departments of Urology and Physiology and Biophysics (ABA, DL), New York-Presbyterian Hospital, Weill Medical College of Cornell University, New York, New York, USA.
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Wang
authors.forename: Andrea
authors.initials: A
authors.lastname: Brenner-Anantharam
authors.forename: E Darracott
authors.initials: ED
authors.lastname: Vaughan
authors.forename: Doris
authors.initials: D
authors.lastname: Herzlinger
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000494:pharmacology; D005260:Female; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D007682:Kidney Pelvis / Q000196:embryology*; D051379:Mice; D009130:Muscle, Smooth / Q000196:embryology*; D014513:Ureter / Q000196:embryology*; D014517:Ureteral Obstruction / Q000209:etiology*; D000099176:Noggin Protein; D016207:Cytokines
chemical_list: D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000099176:Noggin Protein; C525810:Bmp4 protein, mouse; C113178:Grem1 protein, mouse; D016207:Cytokines