The polarity protein VANG-1 antagonizes Wnt signaling by facilitating Frizzled endocytosis

Abstract

Signaling that instructs the migration of neurons needs to be tightly regulated to ensure precise positioning of neurons and subsequent wiring of the neuronal circuits. Wnt-Frizzled signaling controls neuronal migration in metazoans, in addition to many other aspects of neural development. We show that Caenorhabditis elegans VANG-1, a membrane protein that acts in the planar cell polarity (PCP) pathway, antagonizes Wnt signaling by facilitating endocytosis of the Frizzled receptors. Mutations of vang-1 suppress migration defects of multiple classes of neurons in the Frizzled mutants, and overexpression of vang-1 causes neuronal migration defects similar to those of the Frizzled mutants. Our genetic experiments suggest that VANG-1 facilitates Frizzled endocytosis through β-arrestin2. Co-immunoprecipitation experiments indicate that Frizzled proteins and VANG-1 form a complex, and this physical interaction requires the Frizzled cysteine-rich domain. Our work reveals a novel mechanism mediated by the PCP protein VANG-1 that downregulates Wnt signaling through Frizzled endocytosis.

Wnt Signaling Drives Ectopic Gene Expression and Larval Arrest in the Absence of theCaenorhabditis elegansDREAM Repressor Complex

“…Of the five Wnt ligands, EGL-20 has most often been shown to interact with the Wnt/PCP pathway (Green et al 2008;Mentink et al 2018). In the intestine, the only documented role of Wnt/PCP signaling is for proper orientation of intestinal cells during intestinal morphogenesis (Asan et al 2016;Hoffmann et al 2010), but in other tissues Wnt/PCP signaling can help to regulate A-P fate specification (Ackley 2014;Antic et al 2010;He et al 2018;Mattes et al 2018;Mentink et al 2018). It is still unclear what role Wnt/PCP signaling plays in regulating gene expression and fate specification in the intestine.…”

“…The conserved Wnt/PCP component VANG-1 is required for the HTA phenotype, ectopic PGL-1 expression, and small brood size in lin-54 mutants The strong suppression of the HTA phenotype in lin-54 mutants with the knock-down of any of the three Wnt PCP pathway components (vang-1, prkl-1, and fmi-1) led us to further investigate the genetic interaction of the DREAM complex and Wnt/PCP pathway. VANG-1 is the highly conserved C. elegans homolog of the PCP pathway associated transmembrane Vangl protein and it is necessary for mediating PCP signaling (He et al 2018;Honnen et al 2012;Yang and Mlodzik 2015). We crossed vang-1(ok1142) mutation, which lack 162 amino acids of the C-terminus of VANG-1 (Honnen et al 2012), with the lin-54(n2231) mutation to create a lin-54; vang-1 double mutant.…”

Wnt signaling activates gene expression in the absence of theC. elegansDREAM repressor complex in somatic cells

“…Of the five Wnt ligands, EGL-20 has most often been shown to interact with the Wnt/PCP pathway (Green et al 2008;Mentink et al 2018). In the intestine, the only documented role of Wnt/PCP signaling is for proper orientation of intestinal cells during intestinal morphogenesis (Asan et al 2016;Hoffmann et al 2010), but in other tissues Wnt/PCP signaling can help to regulate A-P fate specification (Ackley 2014;Antic et al 2010;He et al 2018;Mattes et al 2018;Mentink et al 2018). It is still unclear what role Wnt/PCP signaling plays in regulating gene expression and fate specification in the intestine.…”

“…The strong suppression of the HTA phenotype in lin-54 mutants with the knockdown of any of the three Wnt PCP pathway components (vang-1, prkl-1, and fmi-1) led us to further investigate the genetic interaction of the DREAM complex and Wnt/PCP pathways. VANG-1 is the highly conserved C. elegans homolog of PCP pathway associated transmembrane Vangl protein necessary for mediating PCP signaling (He et al 2018;Honnen et al 2012;Yang & Mlodzik 2015). We crossed the vang-1(ok1142) mutation, which lacks 162 amino acids of the C-terminus (Honnen et al 2012), to the lin-54 mutant to create a vang-1; lin-54 double mutant.…”

Advances in understanding vertebrate nephrogenesis

“…65 While the core PCP components are known to be needed for proper tissue development, other factors and their downstream consequences are being discovered. [65][66][67][68][69][70] One known factor that regulates kidney PCP is Wnt9b acting via Rho-kinase. [71][72][73] This is an area of intense research as dramatically increased proliferation can result in disease states such as polycystic kidney disease (PKD).…”