title: Nephric duct insertion is a crucial step in urinary tract maturation that is regulated by a Gata3-Raldh2-Ret molecular network in mice.
abstract: Urinary tract development depends on a complex series of events in which the ureter moves from its initial branch point on the nephric duct (ND) to its final insertion site in the cloaca (the primitive bladder and urethra). Defects in this maturation process can result in malpositioned ureters and hydronephrosis, a common cause of renal disease in children. Here, we report that insertion of the ND into the cloaca is an unrecognized but crucial step that is required for proper positioning of the ureter and that depends on Ret signaling. Analysis of Ret mutant mice at birth reveals hydronephrosis and defective ureter maturation, abnormalities that our results suggest are caused, at least in part, by delayed insertion of the ND. We find a similar set of malformations in mutants lacking either Gata3 or Raldh2. We show that these factors act in parallel to regulate ND insertion via Ret. Morphological analysis of ND extension in wild-type embryos reveals elaborate cellular protrusions at ND tips that are not detected in Ret, Gata3 or Raldh2 mutant embryos, suggesting that these protrusions may normally be important for fusion with the cloaca. Together, our studies reveal a novel Ret-dependent event, ND insertion, that, when abnormal, can cause obstruction and hydronephrosis at birth; whether ND defects underlie similar types of urinary tract abnormalities in humans is an interesting possibility.
authors.affiliation: Department of Urology, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Chia
authors.forename: David
authors.initials: D
authors.lastname: Grote
authors.forename: Michael
authors.initials: M
authors.lastname: Marcotte
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Batourina
authors.forename: Cathy
authors.initials: C
authors.lastname: Mendelsohn
authors.forename: Maxime
authors.initials: M
authors.lastname: Bouchard
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D022081:Cell Surface Extensions / Q000378:metabolism / Q000648:ultrastructure; D002988:Cloaca / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005260:Female; D050990:GATA3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006869:Hydronephrosis / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009024:Morphogenesis; D011247:Pregnancy; D051096:Proto-Oncogene Proteins c-ret / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014551:Urinary Tract / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D000445:Aldehyde Oxidoreductases; C470579:RALDH2 protein, mouse; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse