Kidney-specific inactivation of Ofd1 leads to renal cystic disease associated with upregulation of the mTOR pathway

Abstract

The oral-facial-digital type I syndrome (OFDI; MIM 311200) is a rare syndromic form of inherited renal cystic disease. It is transmitted as an X-linked dominant, male lethal disorder and is caused by mutations in the OFD1 gene. Previous studies demonstrated that OFDI belongs to the growing number of disorders ascribed to dysfunction of primary cilia. We generated a conditional inactivation of the mouse Ofd1 gene using the Ksp-Cre transgenic line, which resulted in a viable model characterized by renal cystic disease and progressive impairment of renal function. The study of this model allowed us to demonstrate that primary cilia initially form and then disappear after the development of cysts, suggesting that the absence of primary cilia is a consequence rather than the primary cause of renal cystic disease. Immunofluorescence and western blotting analysis revealed upregulation of the mTOR pathway in both dilated and non-dilated renal structures. Treatment with rapamycin, a specific inhibitor of the mTOR pathway, resulted in a significant reduction in the number and size of renal cysts and a decrease in the cystic index compared with untreated mutant animals, suggesting that dysregulation of this pathway in our model is mTOR-dependent. The animal model we have generated could thus represent a valuable tool to understand the molecular link between mTOR and cyst development, and eventually to the identification of novel drug targets for renal cystic disease.

Mutations in Traf3ip1 reveal defects in ciliogenesis, embryonic development, and altered cell size regulation

“…Deletion of Tsc2 or polycsytin-1 leads to renal cystic disease that is associated with a marked increase in mTor activity. Interestingly, the renal cystic phenotypes observed in cilia protein mutant models such as the orpk ( Ift88 Tg737Rpw ) mice and mice lacking the basal body protein Oral-Facial-Digital type I (OFDI) can be greatly diminished by treatment with rapamycin (Zullo et al, 2010). …”

Centriolar satellites are assembly points for proteins implicated in human ciliopathies, including oral-facial-digital syndrome 1

“…These defects could potentially lead to problems in attachment of the mother centriole to the apical cell surface. It remains possible, however, that the actions of OFD1 are not confined to the generation of cilia because these appear to be present during tubular cystogenesis induced by renal epithelial-specific downregulation of Ofd1 in mice (Zullo et al, 2010). OFD1 protein has also been detected in nuclei as part of the TIP60 chromatin remodelling complex, and thus might play roles in regulating gene expression (Giorgio et al, 2007).…”

OFD1 and Flotillins Are Integral Components of a Ciliary Signaling Protein Complex Organized by Polycystins in Renal Epithelia and Odontoblasts

“…Deletion of the Ofd1 gene (Ofd1Δ4-5/+-) in mice causes missing/supernumerary teeth, enamel hypoplasia, and polycystic kidney disease analogous to human oral-facial-digital syndrome type 1 [4]. The observed morphological defects in molars result from altered differentiation and polarization of odontoblasts when Ofd1 is mutant [3], [4], [8]. Localization of OFD1 to the primary cilium of tooth ectomesenchymal odontoblasts and renal epithelial cells is therefore speculated to be crucial for proper cellular differentiation of both cell types [3], [4].…”