title: Bmp7 functions via a polarity mechanism to promote cloacal septation.
abstract: BACKGROUND
  During normal development in human and other placental mammals, the embryonic cloacal cavity separates along the axial longitudinal plane to give rise to the urethral system, ventrally, and the rectum, dorsally. Defects in cloacal development are very common and present clinically as a rectourethral fistula in about 1 in 5,000 live human births. Yet, the cellular mechanisms of cloacal septation remain poorly understood.
  
  
  RESULTS
  We previously detected Bone morphogenetic protein 7 (Bmp7) expression in the urorectal mesenchyme (URM), and have shown that loss of Bmp7 function results in the arrest of cloacal septation. Here, we present evidence that cloacal partitioning is driven by Bmp7 signaling in the cloacal endoderm. We performed TUNEL and immunofluorescent analysis on cloacal sections from Bmp7 null and control littermate embryos. We found that loss of Bmp7 results in a dramatic decrease in the endoderm survival and a delay in differentiation. We used immunological methods to show that Bmp7 functions by activating the c-Jun N-terminal kinase (JNK) pathway. We carried out confocal and 3D imaging analysis of mitotic chromosome bundles to show that during normal septation cells in the cloacal endoderm divide predominantly in the apical-basal direction. Loss of Bmp7/JNK signaling results in randomization of mitotic angles in the cloacal endoderm. We also conducted immunohistochemical analysis of human fetal sections to show that BMP/phospho-SMAD and JNK pathways function in the human cloacal region similar as in the mouse.
  
  
  CONCLUSIONS
  Our results strongly indicate that Bmp7/JNK signaling regulates remodeling of the cloacal endoderm resulting in a topological separation of the urinary and digestive systems. Our study points to the importance of Bmp and JNK signaling in cloacal development and rectourethral malformations.
authors.affiliation: Department of Urology, School of Medicine, New York University, New York, New York, United States of America.
authors.forename: Kun
authors.initials: K
authors.lastname: Xu
authors.forename: Xinyu
authors.initials: X
authors.lastname: Wu
authors.forename: Ellen
authors.initials: E
authors.lastname: Shapiro
authors.forename: Honging
authors.initials: H
authors.lastname: Huang
authors.forename: Lixia
authors.initials: L
authors.lastname: Zhang
authors.forename: Duane
authors.initials: D
authors.lastname: Hickling
authors.forename: Yan
authors.initials: Y
authors.lastname: Deng
authors.forename: Peng
authors.initials: P
authors.lastname: Lee
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Herbert
authors.initials: H
authors.lastname: Lepor
authors.forename: Irina
authors.initials: I
authors.lastname: Grishina
mesh_terms: D000818:Animals; D019521:Body Patterning; D055419:Bone Morphogenetic Protein 7 / Q000172:deficiency / Q000378:metabolism*; D002454:Cell Differentiation; D002455:Cell Division; D016764:Cell Polarity; D049109:Cell Proliferation; D002470:Cell Survival; D002988:Cloaca / Q000166:cytology* / Q000196:embryology* / Q000201:enzymology; D004707:Endoderm / Q000166:cytology; D004848:Epithelium / Q000196:embryology; D005333:Fetus / Q000196:embryology / Q000201:enzymology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D012007:Rectum / Q000196:embryology / Q000201:enzymology; D051785:Smad Proteins / Q000378:metabolism; D014521:Urethra / Q000196:embryology / Q000201:enzymology
chemical_list: D055419:Bone Morphogenetic Protein 7; D051785:Smad Proteins; D048031:JNK Mitogen-Activated Protein Kinases