Impaired Wnt–β-catenin signaling disrupts adult renal homeostasis and leads to cystic kidney ciliopathy

Abstract

Cystic kidney disease represents a major cause of end-stage renal disease, yet the molecular mechanisms of pathogenesis remain largely unclear. Recent emphasis has been placed on a potential role for canonical Wnt signaling, but investigation of this pathway in adult renal homeostasis is lacking. Here we provide evidence of a previously unidentified canonical Wnt activity in adult mammalian kidney homeostasis, the loss of which leads to cystic kidney disease. Loss of the Jouberin (Jbn) protein in mouse leads to the cystic kidney disease nephronophthisis, owing to an unexpected decrease in endogenous Wnt activity. Jbn interacts with and facilitates β-catenin nuclear accumulation, resulting in positive modulation of downstream transcription. Finally, we show that Jbn is required in vivo for a Wnt response to injury and renal tubule repair, the absence of which triggers cystogenesis.Cystic kidney disorders include autosomal recessive and dominant polycystic kidney diseases as well as nephronophthisis 1,2 . Although the exact causes of these related disorders are not clear, various signaling pathways have been implicated. Specifically, several of the proteins encoded by the nephronophthisis-associated genes have been identified as negative modulators of the canonical Wnt pathway while activating the noncanonical Wnt pathway (planar cell polarity (PCP)) 3,4 , suggesting a specific link between cystic kidney disease and Wnt signaling. The emerging model is that cystogenesis is at least partly due to overactivation of canonical Wnt signaling. This is supported by work with mutants of negative Wnt regulators, which show embryonic kidney cysts 5,6 . However, similar embryonic kidney cysts have also been Correspondence should be addressed to J.G.G. (jogleeson@ucsd.edu). Note: Supplementary information is available on the Nature Medicine website.Author Contributions: M.A.L. designed the experimental approach, conducted the experiments and wrote the manuscript. J.G.G. supervised the project and experimental approach, interpreted data and contributed to manuscript preparation. C.M.L. designed and generated the Ahi1 −/− mouse mutant and provided feedback. J.L.S. generated mutant constructs and assisted in microscopy. L.S. contributed to in vitro localization experiments. M.D. contributed to IRI experiments. S.K.N. provided feedback regarding renal characterization and manuscript preparation. K.W. provided feedback and reagents for in vitro Wnt assays.Published online at http://www.nature.com/naturemedicine/. Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/. NIH Public Access Author ManuscriptNat Med. Author manuscript; available in PMC 2010 July 2. Results Ahi1 −/− mice show pathology consistent with nephronophthisisJbn is the protein product of the AHI1 gene that is mutated in Joubert syndrome 9,10 , a disorder associated with cerebellar hypoplasia, retinitis pigmentosa and nephronophthisis 11 . We used Ahi1-null mice generated by homologous recombination, whi...

LDL Receptor–Related Protein 6 Modulates Ret Proto-Oncogene Signaling in Renal Development and Cystic Dysplasia

“…11 Downregulation of Wnt/b-catenin activities and cystic kidney ciliopathy are observed in the KO mice of Ahi1 that encodes a cilial protein Jouberin and may be genetically interactive with Lrp6 in polycystic kidney disease (PKD) and related cystogenesis. 29 In support of this, a recent study revealed that LRP5 mutations and canonical Wnt signaling are associated with hepatic cystogenesis. 30 However, Wnt/ b-catenin signaling is not involved in renal cystic formation of the mutant mice of Invs that encodes a cilial protein inversin or nephrocystin-2.…”

Cilia in vertebrate development and disease

“…adenomatous polyposis coli, Apc; van gogh-like 2, Vangl2; and -catenin) have been localized to the cilium (Corbit et al, 2008;Ross et al, 2005). Loss of ciliary and basal body proteins results in dysregulation of -catenin signaling (Corbit et al, 2008; Gerdes et al, 2007;Lancaster et al, 2011a;Lancaster et al, 2011b), with concomitant defects in non-canonical signaling (impaired convergent extension movements, neural tube closure failure and disorganization of stereocilia in the mouse inner ear), highlighting an emerging role for the basal body and primary cilium in Wnt/PCP signaling (Ferrante et al, 2009; Gerdes et al, 2007; Hunkapiller et al, 2010;Lancaster et al, 2009;McDermott et al, 2010;Simons et al, 2005).…”

“…adenomatous polyposis coli, Apc; van gogh-like 2, Vangl2; and -catenin) have been localized to the cilium (Corbit et al, 2008;Ross et al, 2005). Loss of ciliary and basal body proteins results in dysregulation of -catenin signaling (Corbit et al, 2008; Gerdes et al, 2007;Lancaster et al, 2011a;Lancaster et al, 2011b), with concomitant defects in non-canonical signaling (impaired convergent extension movements, neural tube closure failure and disorganization of stereocilia in the mouse inner ear), highlighting an emerging role for the basal body and primary cilium in Wnt/PCP signaling (Ferrante et al, 2009; Gerdes et al, 2007; Hunkapiller et al, 2010;Lancaster et al, 2009;McDermott et al, 2010;Simons et al, 2005).The physiological relevance of dysregulated Wnt/PCP signaling is evident in the development and function of several vertebrate organs, such as kidney, cochlea and neural tube. By patterning the planar surface of an epithelium or tissue, PCP proteins, such as disheveled 1 (Dvl1), Dvl2 and Dvl3, can regulate the apical movement of basal bodies from deep within the cytoplasm to the cell surface and, thus, cilia formation and positioning in the Xenopus mucociliary epithelia (Park et al, 2008).…”

Cilia and cell cycle re-entry

“…2A). However, upon canonical Wnt activation, Jbn is released from the cilia via retrograde IFT, which then physically interacts with β-catenin to facilitate its translocalization to the nucleus and activation of β-catenin-dependent transcription of target genes 65,66 (Fig. 2B).…”