SLC20A1 Is Involved in Urinary Tract and Urorectal Development
Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal dev...
Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Frontiers Media S.A.
2020-08-01
|
Series: | Frontiers in Cell and Developmental Biology |
Subjects: | |
Online Access: | https://www.frontiersin.org/article/10.3389/fcell.2020.00567/full |
id |
doaj-9c651c06182b43e58e089d5b84ebbebc |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Johanna Magdalena Rieke Johanna Magdalena Rieke Johanna Magdalena Rieke Rong Zhang Doreen Braun Öznur Yilmaz Anna S. Japp Anna S. Japp Filipa M. Lopes Michael Pleschka Michael Pleschka Alina C. Hilger Alina C. Hilger Sophia Schneider Sophia Schneider William G. Newman Glenda M. Beaman Agneta Nordenskjöld Agneta Nordenskjöld Anne-Karoline Ebert Martin Promm Wolfgang H. Rösch Raimund Stein Karin Hirsch Frank-Mattias Schäfer Eberhard Schmiedeke Thomas M. Boemers Martin Lacher Dietrich Kluth Jan-Hendrik Gosemann Magnus Anderberg Gillian Barker Gundela Holmdahl Göran Läckgren David Keene Raimondo M. Cervellione Elisa Giorgio Elisa Giorgio Massimo Di Grazia Wouter F. J. Feitz Carlo L. M. Marcelis Iris A. L. M. Van Rooij Arend Bökenkamp Goedele M. A. Beckers Catherine E. Keegan Catherine E. Keegan Amit Sharma Amit Sharma Tikam Chand Dakal Lars Wittler Phillip Grote Nadine Zwink Ekkehart Jenetzky Ekkehart Jenetzky Alfredo Brusco Alfredo Brusco Holger Thiele Michael Ludwig Ulrich Schweizer Adrian S. Woolf Adrian S. Woolf Benjamin Odermatt Benjamin Odermatt Heiko Reutter Heiko Reutter |
spellingShingle |
Johanna Magdalena Rieke Johanna Magdalena Rieke Johanna Magdalena Rieke Rong Zhang Doreen Braun Öznur Yilmaz Anna S. Japp Anna S. Japp Filipa M. Lopes Michael Pleschka Michael Pleschka Alina C. Hilger Alina C. Hilger Sophia Schneider Sophia Schneider William G. Newman Glenda M. Beaman Agneta Nordenskjöld Agneta Nordenskjöld Anne-Karoline Ebert Martin Promm Wolfgang H. Rösch Raimund Stein Karin Hirsch Frank-Mattias Schäfer Eberhard Schmiedeke Thomas M. Boemers Martin Lacher Dietrich Kluth Jan-Hendrik Gosemann Magnus Anderberg Gillian Barker Gundela Holmdahl Göran Läckgren David Keene Raimondo M. Cervellione Elisa Giorgio Elisa Giorgio Massimo Di Grazia Wouter F. J. Feitz Carlo L. M. Marcelis Iris A. L. M. Van Rooij Arend Bökenkamp Goedele M. A. Beckers Catherine E. Keegan Catherine E. Keegan Amit Sharma Amit Sharma Tikam Chand Dakal Lars Wittler Phillip Grote Nadine Zwink Ekkehart Jenetzky Ekkehart Jenetzky Alfredo Brusco Alfredo Brusco Holger Thiele Michael Ludwig Ulrich Schweizer Adrian S. Woolf Adrian S. Woolf Benjamin Odermatt Benjamin Odermatt Heiko Reutter Heiko Reutter SLC20A1 Is Involved in Urinary Tract and Urorectal Development Frontiers in Cell and Developmental Biology SLC20A1 urinary tract development kidney formation zebrafish development cloacal malformation functional genetics |
author_facet |
Johanna Magdalena Rieke Johanna Magdalena Rieke Johanna Magdalena Rieke Rong Zhang Doreen Braun Öznur Yilmaz Anna S. Japp Anna S. Japp Filipa M. Lopes Michael Pleschka Michael Pleschka Alina C. Hilger Alina C. Hilger Sophia Schneider Sophia Schneider William G. Newman Glenda M. Beaman Agneta Nordenskjöld Agneta Nordenskjöld Anne-Karoline Ebert Martin Promm Wolfgang H. Rösch Raimund Stein Karin Hirsch Frank-Mattias Schäfer Eberhard Schmiedeke Thomas M. Boemers Martin Lacher Dietrich Kluth Jan-Hendrik Gosemann Magnus Anderberg Gillian Barker Gundela Holmdahl Göran Läckgren David Keene Raimondo M. Cervellione Elisa Giorgio Elisa Giorgio Massimo Di Grazia Wouter F. J. Feitz Carlo L. M. Marcelis Iris A. L. M. Van Rooij Arend Bökenkamp Goedele M. A. Beckers Catherine E. Keegan Catherine E. Keegan Amit Sharma Amit Sharma Tikam Chand Dakal Lars Wittler Phillip Grote Nadine Zwink Ekkehart Jenetzky Ekkehart Jenetzky Alfredo Brusco Alfredo Brusco Holger Thiele Michael Ludwig Ulrich Schweizer Adrian S. Woolf Adrian S. Woolf Benjamin Odermatt Benjamin Odermatt Heiko Reutter Heiko Reutter |
author_sort |
Johanna Magdalena Rieke |
title |
SLC20A1 Is Involved in Urinary Tract and Urorectal Development |
title_short |
SLC20A1 Is Involved in Urinary Tract and Urorectal Development |
title_full |
SLC20A1 Is Involved in Urinary Tract and Urorectal Development |
title_fullStr |
SLC20A1 Is Involved in Urinary Tract and Urorectal Development |
title_full_unstemmed |
SLC20A1 Is Involved in Urinary Tract and Urorectal Development |
title_sort |
slc20a1 is involved in urinary tract and urorectal development |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cell and Developmental Biology |
issn |
2296-634X |
publishDate |
2020-08-01 |
description |
Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC. |
topic |
SLC20A1 urinary tract development kidney formation zebrafish development cloacal malformation functional genetics |
url |
https://www.frontiersin.org/article/10.3389/fcell.2020.00567/full |
work_keys_str_mv |
AT johannamagdalenarieke slc20a1isinvolvedinurinarytractandurorectaldevelopment AT johannamagdalenarieke slc20a1isinvolvedinurinarytractandurorectaldevelopment AT johannamagdalenarieke slc20a1isinvolvedinurinarytractandurorectaldevelopment AT rongzhang slc20a1isinvolvedinurinarytractandurorectaldevelopment AT doreenbraun slc20a1isinvolvedinurinarytractandurorectaldevelopment AT oznuryilmaz slc20a1isinvolvedinurinarytractandurorectaldevelopment AT annasjapp slc20a1isinvolvedinurinarytractandurorectaldevelopment AT annasjapp slc20a1isinvolvedinurinarytractandurorectaldevelopment AT filipamlopes slc20a1isinvolvedinurinarytractandurorectaldevelopment AT michaelpleschka slc20a1isinvolvedinurinarytractandurorectaldevelopment AT michaelpleschka slc20a1isinvolvedinurinarytractandurorectaldevelopment AT alinachilger slc20a1isinvolvedinurinarytractandurorectaldevelopment AT alinachilger slc20a1isinvolvedinurinarytractandurorectaldevelopment AT sophiaschneider slc20a1isinvolvedinurinarytractandurorectaldevelopment AT sophiaschneider slc20a1isinvolvedinurinarytractandurorectaldevelopment AT williamgnewman slc20a1isinvolvedinurinarytractandurorectaldevelopment AT glendambeaman slc20a1isinvolvedinurinarytractandurorectaldevelopment AT agnetanordenskjold slc20a1isinvolvedinurinarytractandurorectaldevelopment AT agnetanordenskjold slc20a1isinvolvedinurinarytractandurorectaldevelopment AT annekarolineebert slc20a1isinvolvedinurinarytractandurorectaldevelopment AT martinpromm slc20a1isinvolvedinurinarytractandurorectaldevelopment AT wolfganghrosch slc20a1isinvolvedinurinarytractandurorectaldevelopment AT raimundstein slc20a1isinvolvedinurinarytractandurorectaldevelopment AT karinhirsch slc20a1isinvolvedinurinarytractandurorectaldevelopment AT frankmattiasschafer slc20a1isinvolvedinurinarytractandurorectaldevelopment AT eberhardschmiedeke slc20a1isinvolvedinurinarytractandurorectaldevelopment AT thomasmboemers slc20a1isinvolvedinurinarytractandurorectaldevelopment AT martinlacher slc20a1isinvolvedinurinarytractandurorectaldevelopment AT dietrichkluth slc20a1isinvolvedinurinarytractandurorectaldevelopment AT janhendrikgosemann slc20a1isinvolvedinurinarytractandurorectaldevelopment AT magnusanderberg slc20a1isinvolvedinurinarytractandurorectaldevelopment AT gillianbarker slc20a1isinvolvedinurinarytractandurorectaldevelopment AT gundelaholmdahl slc20a1isinvolvedinurinarytractandurorectaldevelopment AT goranlackgren slc20a1isinvolvedinurinarytractandurorectaldevelopment AT davidkeene slc20a1isinvolvedinurinarytractandurorectaldevelopment AT raimondomcervellione slc20a1isinvolvedinurinarytractandurorectaldevelopment AT elisagiorgio slc20a1isinvolvedinurinarytractandurorectaldevelopment AT elisagiorgio slc20a1isinvolvedinurinarytractandurorectaldevelopment AT massimodigrazia slc20a1isinvolvedinurinarytractandurorectaldevelopment AT wouterfjfeitz slc20a1isinvolvedinurinarytractandurorectaldevelopment AT carlolmmarcelis slc20a1isinvolvedinurinarytractandurorectaldevelopment AT irisalmvanrooij slc20a1isinvolvedinurinarytractandurorectaldevelopment AT arendbokenkamp slc20a1isinvolvedinurinarytractandurorectaldevelopment AT goedelemabeckers slc20a1isinvolvedinurinarytractandurorectaldevelopment AT catherineekeegan slc20a1isinvolvedinurinarytractandurorectaldevelopment AT catherineekeegan slc20a1isinvolvedinurinarytractandurorectaldevelopment AT amitsharma slc20a1isinvolvedinurinarytractandurorectaldevelopment AT amitsharma slc20a1isinvolvedinurinarytractandurorectaldevelopment AT tikamchanddakal slc20a1isinvolvedinurinarytractandurorectaldevelopment AT larswittler slc20a1isinvolvedinurinarytractandurorectaldevelopment AT phillipgrote slc20a1isinvolvedinurinarytractandurorectaldevelopment AT nadinezwink slc20a1isinvolvedinurinarytractandurorectaldevelopment AT ekkehartjenetzky slc20a1isinvolvedinurinarytractandurorectaldevelopment AT ekkehartjenetzky slc20a1isinvolvedinurinarytractandurorectaldevelopment AT alfredobrusco slc20a1isinvolvedinurinarytractandurorectaldevelopment AT alfredobrusco slc20a1isinvolvedinurinarytractandurorectaldevelopment AT holgerthiele slc20a1isinvolvedinurinarytractandurorectaldevelopment AT michaelludwig slc20a1isinvolvedinurinarytractandurorectaldevelopment AT ulrichschweizer slc20a1isinvolvedinurinarytractandurorectaldevelopment AT adrianswoolf slc20a1isinvolvedinurinarytractandurorectaldevelopment AT adrianswoolf slc20a1isinvolvedinurinarytractandurorectaldevelopment AT benjaminodermatt slc20a1isinvolvedinurinarytractandurorectaldevelopment AT benjaminodermatt slc20a1isinvolvedinurinarytractandurorectaldevelopment AT heikoreutter slc20a1isinvolvedinurinarytractandurorectaldevelopment AT heikoreutter slc20a1isinvolvedinurinarytractandurorectaldevelopment |
_version_ |
1724661446814466048 |
spelling |
doaj-9c651c06182b43e58e089d5b84ebbebc2020-11-25T03:09:58ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2020-08-01810.3389/fcell.2020.00567533864SLC20A1 Is Involved in Urinary Tract and Urorectal DevelopmentJohanna Magdalena Rieke0Johanna Magdalena Rieke1Johanna Magdalena Rieke2Rong Zhang3Doreen Braun4Öznur Yilmaz5Anna S. Japp6Anna S. Japp7Filipa M. Lopes8Michael Pleschka9Michael Pleschka10Alina C. Hilger11Alina C. Hilger12Sophia Schneider13Sophia Schneider14William G. Newman15Glenda M. Beaman16Agneta Nordenskjöld17Agneta Nordenskjöld18Anne-Karoline Ebert19Martin Promm20Wolfgang H. Rösch21Raimund Stein22Karin Hirsch23Frank-Mattias Schäfer24Eberhard Schmiedeke25Thomas M. Boemers26Martin Lacher27Dietrich Kluth28Jan-Hendrik Gosemann29Magnus Anderberg30Gillian Barker31Gundela Holmdahl32Göran Läckgren33David Keene34Raimondo M. Cervellione35Elisa Giorgio36Elisa Giorgio37Massimo Di Grazia38Wouter F. J. Feitz39Carlo L. M. Marcelis40Iris A. L. M. Van Rooij41Arend Bökenkamp42Goedele M. A. Beckers43Catherine E. Keegan44Catherine E. Keegan45Amit Sharma46Amit Sharma47Tikam Chand Dakal48Lars Wittler49Phillip Grote50Nadine Zwink51Ekkehart Jenetzky52Ekkehart Jenetzky53Alfredo Brusco54Alfredo Brusco55Holger Thiele56Michael Ludwig57Ulrich Schweizer58Adrian S. Woolf59Adrian S. Woolf60Benjamin Odermatt61Benjamin Odermatt62Heiko Reutter63Heiko Reutter64Institute of Human Genetics, University Hospital Bonn, Bonn, GermanyInstitute for Anatomy and Cell Biology, University Hospital Bonn, University of Bonn, Bonn, GermanyDepartment of Pediatrics, Children’s Hospital Medical Center, University Hospital Bonn, Bonn, GermanyInstitut für Biochemie und Molekularbiologie, Universitätsklinikum Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, GermanyInstitute of Human Genetics, University Hospital Bonn, Bonn, GermanyInstitute for Anatomy and Cell Biology, University Hospital Bonn, University of Bonn, Bonn, GermanyInstitute of Neuropathology, University of Bonn Medical Center, Bonn, GermanyInstitute of Pathology, University Hospital Düsseldorf, Düsseldorf, GermanyDivision of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology Medicine and Health, School of Biological Sciences, University of Manchester, Manchester, United KingdomInstitute of Human Genetics, University Hospital Bonn, Bonn, GermanyInstitute for Anatomy and Cell Biology, University Hospital Bonn, University of Bonn, Bonn, GermanyInstitute of Human Genetics, University Hospital Bonn, Bonn, GermanyDepartment of Pediatrics, Children’s Hospital Medical Center, University Hospital Bonn, Bonn, GermanyInstitute of Human Genetics, University Hospital Bonn, Bonn, GermanyDepartment of Neonatology and Pediatric Intensive Care, Children’s Hospital Medical Center, University Hospital Bonn, Bonn, GermanyCentre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United KingdomCentre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom0Department of Women’s and Children’s Health, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden1Pediatric Surgery, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden2Department of Urology and Pediatric Urology, University Hospital of Ulm, Ulm, Germany3Department of Pediatric Urology, Clinic St. Hedwig, University Medical Center Regensburg, Regensburg, Germany3Department of Pediatric Urology, Clinic St. Hedwig, University Medical Center Regensburg, Regensburg, Germany4Medical Faculty Mannheim, Centre for Pediatric, Adolescent and Reconstructive Urology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany5Division of Pediatric Urology, Department of Urology, University of Erlangen-Nürnberg, Erlangen, Germany6Department of Pediatric Surgery and Urology, Cnopfsche Kinderklinik, Nürnberg, Germany7Department of Pediatric Surgery and Urology, Center for Child and Youth Health, Klinikum Bremen-Mitte, Bremen, Germany8Department of Pediatric Surgery and Pediatric Urology, Children’s Hospital of Cologne, Cologne, Germany9Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany9Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany9Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany0Department of Pediatric Surgery, Skane University Hospital Lund, Lund, Sweden1Department of Women’s and Children’s Health, Uppsala Academic Children Hospital, Uppsala, Sweden2Department of Pediatric Surgery, Queen Silvias Children’s Hospital, Gothenburg, Sweden3Pediatric Urology, University Children’s Hospital, Uppsala, Sweden4Pediatric Urology, Royal Manchester Children’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom4Pediatric Urology, Royal Manchester Children’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom5Department of Medical Sciences, University of Torino, Turin, Italy6Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Turin, Italy7Pediatric Urology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca’ Granda-Ospedale Maggiore Policlinico, Milan, Italy8Division of Pediatric Urology, Department of Urology, Radboudumc Amalia Children’s Hospital, Nijmegen, Netherlands9Department of Genetics, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands0Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands1Emma Children’s Hospital, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands2Department of Urology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands3Division of Genetics, Department of Pediatrics, University of Michigan, Ann Arbor, MI, United States4Department of Human Genetics, University of Michigan, Ann Arbor, MI, United States5Department of Neurology, University Hospital Bonn, Bonn, Germany6Department of Ophthalmology, University Hospital Bonn, Bonn, Germany7Department of Biotechnology, Mohanlal Sukhadia University Udaipur, Udaipur, India8Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany9Institute of Cardiovascular Regeneration, Center for Molecular Medicine, Goethe University, Frankfurt am Main, Germany0Department of Pediatric and Adolescent Psychiatry and Psychotherapy, University Medical Centre, Johannes Gutenberg University of Mainz, Mainz, Germany0Department of Pediatric and Adolescent Psychiatry and Psychotherapy, University Medical Centre, Johannes Gutenberg University of Mainz, Mainz, Germany1Institute of Integrative Medicine, Witten/Herdecke University, Herdecke, Germany5Department of Medical Sciences, University of Torino, Turin, Italy6Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Turin, Italy2Cologne Center for Genomics, University of Cologne, Cologne, Germany3Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, GermanyInstitut für Biochemie und Molekularbiologie, Universitätsklinikum Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, GermanyDivision of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology Medicine and Health, School of Biological Sciences, University of Manchester, Manchester, United Kingdom4Royal Manchester Children’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United KingdomInstitute for Anatomy and Cell Biology, University Hospital Bonn, University of Bonn, Bonn, Germany5Institute for Neuroanatomy, University Hospital Bonn, University of Bonn, Bonn, GermanyInstitute of Human Genetics, University Hospital Bonn, Bonn, GermanyDepartment of Neonatology and Pediatric Intensive Care, Children’s Hospital Medical Center, University Hospital Bonn, Bonn, GermanyPrevious studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC.https://www.frontiersin.org/article/10.3389/fcell.2020.00567/fullSLC20A1urinary tract developmentkidney formationzebrafish developmentcloacal malformationfunctional genetics |