The Genetic Origins and Complications of Urinary Tract Abnormalities

Hydronephrosis is a common birth defect in humans that is often detected in prenatal or antenatal screening. Hydronephrosis can self-resolve, or can cause kidney damage and end-stage renal disease, however at present there is no way to accurately predict its severity or outcome. Identification of genetic pathways that cause malformations leading to hydronephrosis will be critical for improving diagnosis and treatment. Hydronephrosis can be linked to a number of developmental defects including VUR (backflow of urine from the bladder to the kidney), physical obstruction that blocks the flow of urine from the kidney to the bladder or posterior urethral valves (PUV). PUV affects males, and can lead to renal damage and bladder dysfunction. Despite the seriousness of these abnormalities, little is known about the etiology or anatomical cause of obstruction in PUV. We have established mouse models of obstruction with particular focus on the urogenital sinus, the primordium of the bladder and urethra. ShhCre;RaraDN mutants selectively express a dominant inhibitory form of Rara in urogenital sinus epithelium that blocks retinoid signaling. They display bilateral hydronephrosis and a ureter insertion abnormality that looks remarkably similar to ureterocele. Sall1 is a transcription factor expressed in urogenital sinus mesenchyme. SALL1 mutations in humans cause Townes-Brocks Syndrome, which is characterized by multi-organ abnormalities including kidney hypoplasia, VUR, hydronephrosis, anogenital defects and PUV. Analysis of urinary tract formation reveals defective ureter insertion and gross dilation of the urethra and vas deferens in Sall1 mutants; a phenotype resembling PUV. We will identify the developmental events that lead to these abnormalities and we will generate a conditional allele, by inactivating Sall1 in the urogenital sinus, sparing the kidney, with the goal of generating a model that displays upper urinary tract obstruction that is often associated with PUV in humans, which will be shared with Project 3 (Barasch) in studies evaluating the effects of obstruction on renal function. Finally, we will analyze ureter maturation in human embryos and we will validate expression of urogenital sinus derived genes identified from microarray and RNAseq studies of ShhCre;RaraDN and Sall1 mouse mutants respectively, to evaluate whether their expression is conserved in humans. These sets of validated genes will be shared with the urological community via the GUDMAP website and will be shared with Project 1 (Gharavi) and Pilot 1 (Sanna-Cherchi) in their studies aimed at identification of mutations causing hydronephrosis, VUR and PUV in humans.