Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways

Abstract

Cystic renal diseases are caused by mutations of proteins that share a unique subcellular localization: the primary cilium of tubular epithelial cells. Mutations of the ciliary protein inversin cause nephronophthisis type II, an autosomal recessive cystic kidney disease characterized by extensive renal cysts, situs inversus and renal failure. Here we report that inversin acts as a molecular switch between different Wnt signaling cascades. Inversin inhibits the canonical Wnt pathway by targeting cytoplasmic dishevelled (Dsh or Dvl1) for degradation; concomitantly, it is required for convergent extension movements in gastrulating Xenopus laevis embryos and elongation of animal cap explants, both regulated by noncanonical Wnt signaling. In zebrafish, the structurally related switch molecule diversin ameliorates renal cysts caused by the depletion of inversin, implying that an inhibition of canonical Wnt signaling is required for normal renal development. Fluid flow increases inversin levels in ciliated tubular epithelial cells and seems to regulate this crucial switch between Wnt signaling pathways during renal development.

Phosphorylation‐dependent Akt–Inversin interaction at the basal body of primary cilia

“…Consistent with the observation that INVS acts as a molecular switch between canonical and noncanonical Wnt signaling (Simons et al , 2005; Benzing et al , 2007), WT INVS inhibited Wnt signaling, an effect that was reversed by NPHP2‐related mutant forms of INVS (R899X, Q671X, or R603X), correlating with the expression levels of Dvl. A functional interaction of Wnt signal and Akt via Dvl has previously been suggested (Fukumoto et al , 2001).…”

“…INVS mutations result in NPHP2, an autosomal recessive cystic kidney disease, which leads to severe kidney failure in early childhood (Otto et al , 2003; Tory et al , 2009; Oud et al , 2014). Consistent with the phenotype of Inv −/− mice, an animal model for NPHP2 (Mochizuki et al , 1998; Morgan et al , 2002b; Eley et al , 2004), INVS knockdown by antisense morpholino oligonucleotides causes pronephric cysts in zebra fish (Simons et al , 2005). …”

“…Mutations in the INVS gene are suggested to cause the malfunctioning of primary cilia, resulting in cystic kidney diseases in NPHP2 (Simons et al , 2005; Tory et al , 2009; Oh & Katsanis, 2012; Ong, 2013). The presence of a cilium is thought to be closely related to cell differentiation and the establishment of proper polarity during development (Simons & Walz, 2006).…”

“…Despite the identification of an increasing number of interacting proteins, the physiological function of INVS has not been fully clarified. INVS interacts with Dishevelled (Dvl), activates PCP (planar cell polarity) signaling, and simultaneously downregulates canonical Wnt signaling by targeting Dvl for proteasome‐mediated degradation (Simons et al , 2005). INVS interacts with anaphase‐promoting complex 2 (APC2) through its D‐box motif, suggesting that it is involved in cell cycle regulation (Morgan et al , 2002b).…”

The primary cilium as a gravitational force transducer and a regulator of transcriptional noise

“…For instance, inversin, a protein localized to the primary cilium (Hou et al, 2002;Watanabe et al, 2003), inhibits the canonical WNT pathway and activates the non-canonical WNT pathway (Simons et al, 2005). In this way, inversin functions as a molecular switch between the two pathways by targeting the WNT pathway protein disheveled (DVL) for degradation.…”