Congenital anomalies of kidney and lower urinary tract (CAKUT) are common malformations (10% of live births) and the most common cause of renal failure in children. In some cases these are incompatible with life and even after surgical correction, many patients progress to renal failure or have associated comorbidities that include skeletal, cardiovascular and hematopoietic systems. A significant impact can be made by understanding the pathogenetic mechanisms that lead to these conditions. Glial cell line-derived neurotrophic factor (GDNF), its coreceptor GFR11 and receptor tyrosine kinase RET constitute a signaling system that is critical for development of the kidneys and the urinary tract. In mice, deletion of Gdnf, Gfr11 or Ret results in perinatal lethality due to renal agenesis. This phenotype is due to failure of induction of the definitive kidney from the ureteric bud (UB) during embryogenesis. We have recently made an exciting discovery that the major Ret docking tyrosines have distinct functions in kidney development. For example, abrogating signals through RetY1015 (PLC3 pathway) results in hypoplastic, multicystic, multiplex kidneys with megaureter and failure of gonads to separate from the ureters;highly reminiscent of CAKUT. While, RetY1062F mutation (disrupts PI3K/MAPK pathways) results in rudimentary kidneys or agenesis. The underlying mechanisms and molecular signals that lead to such complicated developmental abnormalities are not entirely clear. Because Ret signaling components are expressed throughout kidney development, the renal agenesis and lethality has been an obstacle to determine the role of this signaling pathway in kidney development after UB induction. Our hypothesis is that Gfr11-Ret signaling has critical roles in later kidney development, and delineating mechanisms of anomalies observed in Ret-mutant mice will provide key insights into kidney development and pathogenesis of CAKUT. We will use unique animal models to enable us to test these hypotheses.
In Specific Aim 1 we will use Ret reporter and RetY1015F mice to delineate abnormalities in the anterior Wolffian duct, UB position and distal ureter maturation that lead to CAKUT-like defects in these mice. We will use molecular techniques to identify known and novel signals that are aberrantly expressed in Y1015F and Y1062 mutations that may provide insights into basis for these abnormalities.
In Specific Aim 2 we will use Ret-conditional mice to determine the impact of its loss on kidney development after initial UB induction and then identify the key signaling cascades that are important for Ret's function in kidney branching morphogenesis and nephrogenesis.
In Aim 3, we will use Gfr11 conditional mice to determine its unique (because it has broader expression than Ret) and redundant roles with Ret and if trans Gfr11 signaling is important in the kidney. The insights gleaned will enhance our knowledge of Ret signaling specificity and requirement in the developing kidneys and lower urinary tract and better understanding of CAKUT.

Public Health Relevance

Abnormal function of Gdnf, Gfr11 and Ret proteins causes a vast number of kidney defects in mice that are similar to those seen in human patients. In this proposal we will use unique animal models that we have generated to understand the mechanism of how these abnormalities develop when specific functions of these proteins are disrupted. The insights gleaned will provide a better understanding of mechanisms underlying Urogenital system defects with the possibility of early diagnosis and treatment.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-RUS-B (04))
Program Officer
Hoshizaki, Deborah K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
Zip Code
Gou-Fàbregas, Myriam; Macià, Anna; Anerillas, Carlos et al. (2016) 7-dehydrocholesterol efficiently supports Ret signaling in a mouse model of Smith-Opitz-Lemli syndrome. Sci Rep 6:28534
Reginensi, Antoine; Hoshi, Masato; Boualia, Sami Kamel et al. (2015) Yap and Taz are required for Ret-dependent urinary tract morphogenesis. Development 142:2696-703
Davis, T Keefe; Hoshi, Masato; Jain, Sanjay (2014) To bud or not to bud: the RET perspective in CAKUT. Pediatr Nephrol 29:597-608
Gaut, Joseph P; Crimmins, Dan L; Ohlendorf, Matt F et al. (2014) Development of an immunoassay for the kidney-specific protein myo-inositol oxygenase, a potential biomarker of acute kidney injury. Clin Chem 60:747-57
Jain, Sanjay; Noordam, Michiel J; Hoshi, Masato et al. (2014) Validating single-cell genomics for the study of renal development. Kidney Int 86:1049-55
Golden, Judith P; Demaro 3rd, Joseph A; Knoten, Amanda et al. (2013) Dopamine-dependent compensation maintains motor behavior in mice with developmental ablation of dopaminergic neurons. J Neurosci 33:17095-107
Liapis, Helen; Jain, Sanjay (2013) The interface of genetics with pathology in alport nephritis. J Am Soc Nephrol 24:1925-7
Keefe Davis, T; Hoshi, Masato; Jain, Sanjay (2013) Stage specific requirement of Gfr?1 in the ureteric epithelium during kidney development. Mech Dev 130:506-18
Krentz, Anthony D; Murphy, Mark W; Zhang, Teng et al. (2013) Interaction between DMRT1 function and genetic background modulates signaling and pluripotency to control tumor susceptibility in the fetal germ line. Dev Biol 377:67-78
Chatterjee, Rajshekhar; Ramos, Enrique; Hoffman, Mary et al. (2012) Traditional and targeted exome sequencing reveals common, rare and novel functional deleterious variants in RET-signaling complex in a cohort of living US patients with urinary tract malformations. Hum Genet 131:1725-38

Showing the most recent 10 out of 20 publications