title: Multimodal Eph/Ephrin signaling controls several phases of urogenital development.
abstract: A substantial portion of the human population is affected by urogenital birth defects resulting from a failure in ureter development. Although recent research suggests roles for several genes in facilitating the ureter/bladder connection, the underlying molecular mechanisms remain poorly understood. Signaling via Eph receptor tyrosine kinases is involved in several developmental processes. Here we report that impaired Eph/Ephrin signaling in genetically modified mice results in severe hydronephrosis caused by defective ureteric bud induction, ureter maturation, and translocation. Our data imply that ureter translocation requires apoptosis in the urogenital sinus and inhibition of proliferation in the common nephric duct. These processes were disturbed in EphA4/EphB2 compound knockout mice and were accompanied by decreased ERK-2 phosphorylation. Using a set of Eph, Ephrin, and signaling-deficient mutants, we found that during urogenital development, different modes of Eph/Ephrin signaling occur at several sites with EphrinB2 and EphrinA5 acting in concert. Thus, Eph/Ephrin signaling should be considered in the etiology of congenital kidney and urinary tract anomalies.
authors.affiliation: Department of Neuroscience, Developmental Genetics, Uppsala University, Uppsala, Sweden. Electronic address: c.peuckert@neuro.uu.se.
authors.forename: Christiane
authors.initials: C
authors.lastname: Peuckert
authors.affiliation: Department of Neuroscience, Developmental Genetics, Uppsala University, Uppsala, Sweden.
authors.forename: Bejan
authors.initials: B
authors.lastname: Aresh
authors.affiliation: Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.
authors.forename: Pavlo
authors.initials: P
authors.lastname: Holenya
authors.affiliation: Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Adams
authors.affiliation: Department of Neuroscience, Developmental Genetics, Uppsala University, Uppsala, Sweden.
authors.forename: Smitha
authors.initials: S
authors.lastname: Sreedharan
authors.affiliation: Max-Planck Institute of Neurobiology, Martinsried, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Porthin
authors.affiliation: Department of Anatomy and Cell Biology, Göteborg University, Göteborg, Sweden.
authors.forename: Louise
authors.initials: L
authors.lastname: Andersson
authors.affiliation: Department of Neuroscience, Developmental Genetics, Uppsala University, Uppsala, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Pettersson
authors.affiliation: Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wölfl
authors.affiliation: Max-Planck Institute of Neurobiology, Martinsried, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Klein
authors.affiliation: Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine, USA.
authors.forename: Leif
authors.initials: L
authors.lastname: Oxburgh
authors.affiliation: Department of Neuroscience, Developmental Genetics, Uppsala University, Uppsala, Sweden.
authors.forename: Klas
authors.initials: K
authors.lastname: Kullander
mesh_terms: D000818:Animals; D017209:Apoptosis; D036386:Ephrin-A5 / Q000378:metabolism*; D036388:Ephrin-B2 / Q000378:metabolism*; D006801:Humans; D006869:Hydronephrosis / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000196:embryology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009924:Organ Culture Techniques; D038081:Organogenesis / Q000235:genetics; D010766:Phosphorylation; D036122:Receptor, EphA4 / Q000235:genetics / Q000378:metabolism*; D036183:Receptor, EphB2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014513:Ureter / Q000196:embryology; D014564:Urogenital Abnormalities / Q000235:genetics* / Q000378:metabolism
chemical_list: C000601240:EFNB2 protein, mouse; D036386:Ephrin-A5; D036388:Ephrin-B2; C586311:Ephb2 protein, mouse; D036122:Receptor, EphA4; D036183:Receptor, EphB2; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1
keywords: CAKUT; Eph; Ephrin; common nephric duct; ureteric bud; urogenital sinus