Mammalian renal development is dependent on the ureteric bud. Its proximal tip induces nephron formation in the developing kidney and undergoes branching morphogenesis forming the intra-renal collecting system whereas its distal or trunk domain differentiates into the ureter. Abnormal regulation of ureteric bud morphogenesis can result in a spectrum of congenital defects, the most common being ureteral duplications and obstructions. Yet the tissue interactions and signaling pathways that limit ureter number and control ureteral smooth muscle differentiation required for the un-obstructed flow of urine to the bladder remain poorly understood. This proposal is focused on ureter morphogenesis.
In Aim 1, the role of Bmp signaling in restricting ureteric bud outgrowth to a single site along the urinary tract and in controlling ureteral smooth muscle differentiation will be analyzed in mice with a severe knockdown in Bmp4 gene dosage that supports embryonic viability to birth, but not beyond. Inducible Bmp4 knockdown will be accomplished using Cre-lox technology and existing mouse lines. Bmp4 will be knocked down at different stages of development to analyze the role of this signaling factor in regulating ureter number separately, from its role in controlling terminal ureter differentiation.
In Aim 2, we will analyze a mouse line lacking expression of Pbx1, a hox gene cofactor. We have discovered that Pbx1 is essential for restricting Bmp4 signaling and smooth muscle formation to the ureter. This mutant line will be used to dissect the genetic pathways and cell type (s) that control the organization of smooth muscle at the border between the kidney and the ureter, the most common site of urinary tract obstructions in newborns. The successful completion of these experiments will provide insight into the susceptibility of ureter morphogenesis to congenital defects.
The ureter, a muscular tube that transports waste products from the kidneys to the bladder, is highly prone to congenital defects in humans. However, the mechanisms guiding ureter formation in the developing embryo remain poorly understood. In this proposal, we will test several hypotheses explaining the susceptibility of this urinary tract segment to defects.
|Hurtado, Romulo; Bub, Gil; Herzlinger, Doris (2010) The pelvis-kidney junction contains HCN3, a hyperpolarization-activated cation channel that triggers ureter peristalsis. Kidney Int 77:500-8|