title: Wnt5a Deficiency Leads to Anomalies in Ureteric Tree Development, Tubular Epithelial Cell Organization and Basement Membrane Integrity Pointing to a Role in Kidney Collecting Duct Patterning.
abstract: The Wnts can be considered as candidates for the Congenital Anomaly of Kidney and Urinary Tract, CAKUT diseases since they take part in the control of kidney organogenesis. Of them Wnt5a is expressed in ureteric bud (UB) and its deficiency leads to duplex collecting system (13/90) uni- or bilateral kidney agenesis (10/90), hypoplasia with altered pattern of ureteric tree organization (42/90) and lobularization defects with partly fused ureter trunks (25/90) unlike in controls. The UB had also notably less tips due to Wnt5a deficiency being at E15.5 306 and at E16.5 765 corresponding to 428 and 1022 in control (p<0.02; p<0.03) respectively. These changes due to Wnt5a knock out associated with anomalies in the ultrastructure of the UB daughter epithelial cells. The basement membrane (BM) was malformed so that the BM thickness increased from 46.3 nm to 71.2 nm (p<0.01) at E16.5 in the Wnt5a knock out when compared to control. Expression of a panel of BM components such as laminin and of type IV collagen was also reduced due to the Wnt5a knock out. The P4ha1 gene that encodes a catalytic subunit of collagen prolyl 4-hydroxylase I (C-P4H-I) in collagen synthesis expression and the overall C-P4H enzyme activity were elevated by around 26% due to impairment in Wnt5a function from control. The compound Wnt5a+/-;P4ha1+/- embryos demonstrated Wnt5a-/- related defects, for example local hyperplasia in the UB tree. A R260H WNT5A variant was identified from renal human disease cohort. Functional studies of the consequence of the corresponding mouse variant in comparison to normal ligand reduced Wnt5a-signalling in vitro. Together Wnt5a has a novel function in kidney organogenesis by contributing to patterning of UB derived collecting duct development contributing putatively to congenital disease.
authors.affiliation: Laboratory of Developmental Biology, Oulu Centre for Cell-Matrix Research, Biocenter Oulu and Infotech Oulu, and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Pietilä
authors.affiliation: Laboratory of Developmental Biology, Oulu Centre for Cell-Matrix Research, Biocenter Oulu and Infotech Oulu, and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
authors.forename: Renata
authors.initials: R
authors.lastname: Prunskaite-Hyyryläinen
authors.affiliation: Laboratory of Developmental Biology, Oulu Centre for Cell-Matrix Research, Biocenter Oulu and Infotech Oulu, and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
authors.forename: Susanna
authors.initials: S
authors.lastname: Kaisto
authors.affiliation: Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Elisavet
authors.initials: E
authors.lastname: Tika
authors.affiliation: Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Albertien M
authors.initials: AM
authors.lastname: van Eerde
authors.affiliation: Oulu Centre for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
authors.forename: Antti M
authors.initials: AM
authors.lastname: Salo
authors.affiliation: Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Garma
authors.affiliation: Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Miinalainen
authors.affiliation: Department of Urology, Radboudumc Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Wout F
authors.initials: WF
authors.lastname: Feitz
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Ernie M H F
authors.initials: EM
authors.lastname: Bongers
authors.affiliation: Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
authors.forename: André
authors.initials: A
authors.lastname: Juffer
authors.affiliation: Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Nine V A M
authors.initials: NV
authors.lastname: Knoers
authors.affiliation: Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Kirsten Y
authors.initials: KY
authors.lastname: Renkema
authors.affiliation: Oulu Centre for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Myllyharju
authors.affiliation: Laboratory of Developmental Biology, Oulu Centre for Cell-Matrix Research, Biocenter Oulu and Infotech Oulu, and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
authors.forename: Seppo J
authors.initials: SJ
authors.lastname: Vainio
mesh_terms: D000293:Adolescent; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D002648:Child; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D007685:Kidney Tubules, Collecting / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D009154:Mutation / Q000235:genetics; D011487:Protein Conformation; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014513:Ureter / Q000196:embryology* / Q000378:metabolism*; D014564:Urogenital Abnormalities / Q000503:physiopathology*; D014718:Vesico-Ureteral Reflux / Q000503:physiopathology*; D051153:Wnt Proteins / Q000737:chemistry / Q000502:physiology*; D000071818:Wnt-5a Protein; D060528:Wnt4 Protein / Q000502:physiology
chemical_list: D012333:RNA, Messenger; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; C438615:Wnt5a protein, mouse