Abstract
Background: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.Results: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.Conclusions: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.
Highlights
Developmental abnormalities of the kidney underlie a diverse array of human diseases
The reduced kidney sizes and partially penetrant renal aplasia in Esrp1-null mutants strongly suggest that alterations in the expression or splicing of Esrp1-regulated targets lead to these kidney defects
Taken together with the increased incidence of renal aplasia in Esrp1-null mice, these findings suggest that Esrp1 is critical for fibroblast growth factor receptor 2 (Fgfr2) splicing in the ureteric epithelium to maintain ureteric epithelial architecture
Summary
Developmental abnormalities of the kidney underlie a diverse array of human diseases. Numerous congenital abnormalities and genetic diseases that cause renal failure are due to mutations in key developmental genes. 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. Three-dimensional imaging showed that embryonic Esrp knockout (KO) kidneys had fewer ureteric tips and reduced nephron numbers. Conclusions: Our findings reveal that Esrp1-regulated splicing in ureteric epithelial cells plays an important role in renal development. Defects in Esrp KO kidneys likely reflect reduced and/or absent ureteric branching, leading to decreased nephron induction secondary to incorrect Fgfr splicing and other splicing alterations. Developmental Dynamics published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists
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