Severe reductions in nephron number, characteristic of renal hypoplasia/dysplasia, are the leading cause of childhood renal failure. More subtle defects in nephron number have been associated with the development of adult-onset essential hypertension and chronic renal failure. The balance of GLI activator and repressor activities is critical during renal morphogenesis. Mutations that are predicted to generate a truncated protein similar in size to GLI3 repressor are observed in humans with Pallister-Hall Syndrome and renal dysplasia. The Ginsenoside-F4 pathogenic role of constitutive GLI3 repressor activity during renal morphogenesis is further demonstrated by the renal dysplastic phenotype in mice engineered to express GLI3 repressor in a dominant manner and in Shh-deficient mice. Dysplastic Folinic acid calcium salt pentahydrate kidney tissue in Shh-deficient mice is characterized by sustained GLI3 repressor expression in the face of decreased levels of GLI activators, resulting in a shift in the balance of GLI activators and GLI repressors in favor of repressor. Remarkably, genetic elimination 
of Gli3 in the Shh null background restores expression of GLI activators and normalizes renal morphogenesis. The expression of Shh in ureteric cells suggests that it may control renal development via direct effects in the ureteric cell lineage. While conditional inactivation of Shh in ureteric cells results in renal hypoplasia, characterized by reduced kidney size and glomerular number, the dependency of this pathogenic phenotype on Shh signaling in ureteric cells is unknown. Here we define the specific function of HH signaling in the ureteric cell lineage during murine kidney development, in genetic models of deficient or constitutively active signaling. HH signaling activity is specifically restricted to the ureteric cells of the medulla and ureter but is absent from the ureteric cell tips of the renal cortex. Genetic inactivation of Smo in the ureteric cell lineage exerted no deleterious effects on renal morphogenesis. In contrast, genetic inactivation of Ptc1 in the ureteric cell lineage caused ectopic HH signaling activity in ureteric tip cells, impaired ureteric tip cell-specific gene expression and renal hypoplasia. Genetic inactivation of Gli3 alone, the primary GLI repressor, resulted in a similar phenotype suggesting a critical role for GLI3 repressor. Indeed, introduction of a constitutively active GLI3 repressor in a Ptc1-deficienct background normalized the renal phenotype, restored the normal domain of HH signaling activity and rescued expression of genes specific to ureteric tip cells and required for their functions. We propose a model in which SHH-SMO signaling controls the spatial generation of GLI3 repressor, which is required in the cortical ureteric cells for ureteric tip cell-specific gene expression and cell function. Disruption of renal development in humans with Pallister-Hall Syndrome and truncating GLI3 mutations and mice with elevated levels of GLI3 repressor provides compelling evidence in favor of a critical role for GLI3-dependent signaling during mesenchymal-epithelial interactions during early stages of metanephric development. However, the functions of HH signaling during subsequent morphogenic events including nephrogenesis are unknown. Here, we demonstrate that domains of GLI-dependent activator and repressor function are spatially patterned during renal morphogenesis. We investigated the functional significance of these domains in the ureteric cell lineage using genetic murine models of deficient or constitutively active HH signaling. Smodeficiency targeted to the ureteric cell lineage does not disrupt kidney development.