title: Ablation of the epithelial-specific splicing factor Esrp1 results in ureteric branching defects and reduced nephron number.
abstract: Abnormalities in ureteric bud (UB) branching morphogenesis lead to congenital anomalies of the kidney and reduced nephron numbers associated with chronic kidney disease (CKD) and hypertension. Previous studies showed that the epithelial fibroblast growth factor receptor 2 (Fgfr2) IIIb splice variant supports ureteric morphogenesis in response to ligands from the metanephric mesenchyme during renal organogenesis. The epithelial-specific splicing regulator Esrp1 is required for expression of Fgfr2-IIIb and other epithelial-specific splice variants. Our objective was to determine whether Esrp1 is required for normal kidney development.
  
  
  
  Ablation of Esrp1 in mice, alone or together with its paralog Esrp2, was associated with reduced kidney size and increased incidence of renal aplasia. Three-dimensional imaging showed that embryonic Esrp1 knockout (KO) kidneys had fewer ureteric tips and reduced nephron numbers. Analysis of alternative splicing in Esrp-null ureteric epithelial cells by RNA-Seq confirmed a splicing switch in Fgfr2 as well as numerous other transcripts.
  
  
  
  Our findings reveal that Esrp1-regulated splicing in ureteric epithelial cells plays an important role in renal development. Defects in Esrp1 KO kidneys likely reflect reduced and/or absent ureteric branching, leading to decreased nephron induction secondary to incorrect Fgfr2 splicing and other splicing alterations. Developmental Dynamics 245:991-1000, 2016. © 2016 The Authors. Developmental Dynamics published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.
authors.affiliation: Department of Medicine (Renal Division), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Bebee
authors.affiliation: Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Sunder
authors.initials: S
authors.lastname: Sims-Lucas
authors.affiliation: Department of Computer Engineering and Computer Science, KBRIN Bioinformatics Core, University of Louisville, Louisville, Kentucky.
authors.forename: Juw Won
authors.initials: JW
authors.lastname: Park
authors.affiliation: Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bushnell
authors.affiliation: Department of Medicine (Renal Division), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Cieply
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, California.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. russcars@upenn.edu.|Rangos Research Center, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania. russcars@upenn.edu.
authors.forename: Carlton M
authors.initials: CM
authors.lastname: Bates
authors.affiliation: Department of Medicine (Renal Division), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. batescm@upmc.edu.|Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. batescm@upmc.edu.
authors.forename: Russ P
authors.initials: RP
authors.lastname: Carstens
mesh_terms: D000818:Animals; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D007668:Kidney / Q000166:cytology / Q000196:embryology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009399:Nephrons / Q000166:cytology / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics / Q000502:physiology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014513:Ureter / Q000166:cytology* / Q000378:metabolism*
chemical_list: C000588453:ESRP1 protein, mouse; C000607388:ESRP2 protein, mouse; D016601:RNA-Binding Proteins
keywords: alternative splicing; epithelial splicing regulatory proteins; fibroblast growth factor receptors; kidney development