Wnt proteins are lipid modified glycoproteins that play a central role in development, adult tissue homeostasis and disease. Secretion of Wnt proteins is mediated by the Wnt-binding protein Wntless (Wls), which transports Wnt from the Golgi network to the cell surface for release. It has recently been shown that recycling of Wls through a retromer-dependent endosome-to-Golgi trafficking pathway is required for efficient Wnt secretion, but the mechanism of this retrograde transport pathway is poorly understood. Here, we report that Wls recycling is mediated through a novel retromer pathway that is independent of the retromer sorting nexins SNX1-SNX2 and SNX5-SNX6. We found that the unrelated sorting nexin, SNX3, has an evolutionarily conserved function in Wls recycling and Wnt secretion and show that SNX3 interacts directly with the cargo-selective sub-complex of the retromer to sort Wls into a morphologically distinct retrieval pathway. These results demonstrate that SNX3 is part of an alternative retromer pathway that functionally separates the retrograde transport of Wls from other retromer cargo.

Wnt proteins are secreted signaling molecules that play a central role in development and adult tissue homeostasis. We have previously shown that Wnt signaling requires retromer function in Wnt-producing cells. The retromer is a multiprotein complex that mediates endosome-to-Golgi transport of specific sorting receptors. MIG-14/Wls is a conserved transmembrane protein that binds Wnt and is required in Wnt-producing cells for Wnt secretion. Here, we demonstrate that in the absence of retromer function, MIG-14/Wls is degraded in lysosomes and becomes limiting for Wnt signaling. We show that retromer-dependent recycling of MIG-14/Wls is part of a trafficking pathway that retrieves MIG-14/Wls from the plasma membrane. We propose that MIG-14/Wls cycles between the Golgi and the plasma membrane to mediate Wnt secretion. Regulation of this transport pathway may enable Wnt-producing cells to control the range of Wnt signaling in the tissue.

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beta-Catenin signaling determines the proximal-distal axis of the C. elegans gonad by promoting distal fate in asymmetrically dividing somatic gonad precursor cells (SGPs). Impaired function of the Wnt effector POP-1/TCF, its coactivator SYS-1/beta-catenin, and of upstream components including beta-catenin WRM-1 causes all SGP daughters to adopt the proximal fate. Consequently, no distal tip cells (DTCs) that would lead differentiation of gonad arms form in the affected hermaphrodites. Here, we show that deficiency of the nuclear receptor NHR-25 has the opposite effect: extra DTCs develop instead of proximal cells. NHR-25 knockdown restores DTC formation and fertility in pop-1 and sys-1 mutants, suggesting that a balance between NHR-25 and beta-catenin pathway activities is required to establish both proximal and distal fates. This balance relies on direct crossregulation between NHR-25 and the distinct beta-catenin proteins WRM-1 and SYS-1. The nuclear receptor-beta-catenin interaction may be an ancient mechanism of cell-fate decision.