Paul, Binu M.

Cux1 is a homeobox gene involved in cell cycle regulation and kidney development. Cux1 is upregulated in the kidneys of both mice and humans with autosomal dominant polycystic kidney disease (ADPKD). However, Cux1 transgenic mice do not develop cystic kidneys, indicating that upregulation of Cux1 alone is insufficient to develop PKD. Mice carrying a deletion of the C‐terminus of Cux1 (Cux1 tm2Ejn‐/‐ ) express a truncated protein that does not localize to the nucleus, resulting in functional loss of Cux1 transcriptional activity. To test the hypothesis that Cux1 is required to develop PKD, we generated collecting duct specific Pkd1 mutant mice (Pkd1 CD ) that were also homozygous for the Cux1 mutation. When kidneys isolated from newborn Pkd1 CD /Cux1 tm2Ejn ‐/‐ mice were examined, we found a marked reduction in cystic dilations compared to the kidneys isolated from newborn Pkd1 CD mice. We confirmed the Cre activity by crossing the Pkd1 CD and Pkd1 CD / Cux1 tm2Ejn ‐/‐ mice to the membrane‐targeted Tomato/Green Fluorescent Protein (mT/mG) double fluorescent reporter mouse strain (Gt(ROSA)26Sor tm4(ACTB‐tdTomato,‐EGFP)Luo /J), which carries a loxP‐flanked Tomato cassette. Immunofluorescence of kidney sections indicated that collecting duct derived cysts were positive for the excision event in the Pkd1 CD mice. In contrast, although collecting ducts were positive for the excision event in Pkd1 CD / Cux1 tm2Ejn ‐/‐ mice, none of the positive tubules were cystic. Taken together, our results suggest that Cux1 gene dosage influences the progression of cystic disease in an ADPKD mouse model.

Polycystic kidney disease (PKD) is a life‐threatening genetic disorder characterized by the presence of fluid‐filled cysts primarily in the kidneys. PKD can be inherited as autosomal recessive (ARPKD) or autosomal dominant (ADPKD) traits. Mutations in either the PKD1 or PKD2 genes, which encode polycystin 1 and polycystin 2, are the underlying cause of ADPKD. Progressive cyst formation and renal enlargement lead to renal insufficiency in these patients, which need to be managed by lifelong dialysis or renal transplantation. While characteristic features of PKD are abnormalities in epithelial cell proliferation, fluid secretion, extracellular matrix and differentiation, the molecular mechanisms underlying these events are not understood. Here we review the progress that has been made in defining the function of the polycystins, and how disruption of these functions may be involved in cystogenesis. WIREs Dev Biol 2014, 3:465–487. doi: 10.1002/wdev.152This article is categorized under: Signaling Pathways > Global Signaling Mechanisms Birth Defects > Organ Anomalies