THE GENETIC ORIGINS AND COMPLICATIONS OF URINARY TRACT ABNORMALITIES
PI: Cathy Mendelsohn, PhD
Co-Investigator: Hanbin Dan, PhD
Hydronephrosis is a common birth defect that can be linked to a number of developmental abnormalities, 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), a form of outlet obstruction. PUV affects males, and is a major cause of end-stage renal disease in children. 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 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. 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.