title: Wnt11 and Ret/Gdnf pathways cooperate in regulating ureteric branching during metanephric kidney development.
abstract: Reciprocal cell-cell interactions between the ureteric epithelium and the metanephric mesenchyme are needed to drive growth and differentiation of the embryonic kidney to completion. Branching morphogenesis of the Wolffian duct derived ureteric bud is integral in the generation of ureteric tips and the elaboration of the collecting duct system. Wnt11, a member of the Wnt superfamily of secreted glycoproteins, which have important regulatory functions during vertebrate embryonic development, is specifically expressed in the tips of the branching ureteric epithelium. In this work, we explore the role of Wnt11 in ureteric branching and use a targeted mutation of the Wnt11 locus as an entrance point into investigating the genetic control of collecting duct morphogenesis. Mutation of the Wnt11 gene results in ureteric branching morphogenesis defects and consequent kidney hypoplasia in newborn mice. Wnt11 functions, in part, by maintaining normal expression levels of the gene encoding glial cell-derived neurotrophic factor (Gdnf). Gdnf encodes a mesenchymally produced ligand for the Ret tyrosine kinase receptor that is crucial for normal ureteric branching. Conversely, Wnt11 expression is reduced in the absence of Ret/Gdnf signaling. Consistent with the idea that reciprocal interaction between Wnt11 and Ret/Gdnf regulates the branching process, Wnt11 and Ret mutations synergistically interact in ureteric branching morphogenesis. Based on these observations, we conclude that Wnt11 and Ret/Gdnf cooperate in a positive autoregulatory feedback loop to coordinate ureteric branching by maintaining an appropriate balance of Wnt11-expressing ureteric epithelium and Gdnf-expressing mesenchyme to ensure continued metanephric development.
authors.affiliation: Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA.
authors.forename: Arindam
authors.initials: A
authors.lastname: Majumdar
authors.forename: Seppo
authors.initials: S
authors.lastname: Vainio
authors.forename: Andreas
authors.initials: A
authors.lastname: Kispert
authors.forename: Jill
authors.initials: J
authors.lastname: McMahon
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D003433:Crosses, Genetic; D018507:Gene Expression Regulation, Developmental; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006023:Glycoproteins / Q000502:physiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007668:Kidney / Q000196:embryology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D009414:Nerve Growth Factors / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051096:Proto-Oncogene Proteins c-ret; D012313:RNA / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014513:Ureter / Q000196:embryology*; D051153:Wnt Proteins
chemical_list: C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006023:Glycoproteins; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D012313:RNA; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C494999:Ret protein, mouse