Regulation of Wnt protein secretion and its role in gradient formation

Abstract

In metazoans, many developmental and disease-related processes are mediated by Wnt proteins, which are secreted by specific cells to regulate cellular programmes in the surrounding tissue. Although the Wnt-induced signal-transduction cascades are well studied, little is known about how Wnts are secreted. The discovery of Porcupine, an endoplasmic-reticulum-resident acyltransferase, led to closer inspection of the secretory routes of Wnts, and the analysis of Wnt secretion has become an exciting new area of research. Wnt post-translational modifications, interaction partners and subcellular localizations now indicate that Wnt release is tightly regulated. In this review, we summarize recent advances in the field of Wnt secretion and discuss the possibility that separate pathways might regulate the release of lipid-linked morphogens for short-range and long-range signalling.

Figure 1

Putative structure and localization of Evi/Wls/Sprinter. (A) Possible topology of Evi. Conserved cysteine residues (yellow) and a putative signal peptide cleavage site (red arrowhead) are indicated. (B) Human Evi–EGFP or Drosophila Evi–EGFP fusion proteins (green) localize to membranes in unpolarized human HEK293T or Drosophila S2R⁺ cells, respectively. (C) In polarized Drosophila follicle cells, Evi–EGFP expressed under the control of the tubulin promoter, is concentrated at the apical (Ap) side, but is largely absent from the basal side (arrow). A confocal section through an egg chamber is shown. The follicle cells surround the oocyte with their apical side facing the centre of the egg chamber. DNA is shown in blue. Evi, Evenness interrupted; Wls, Wntless.

Figure 2

Models of Evi/Wls/Sprinter-dependent Wnt secretion. Wnt is lipid-modified in the endoplasmic reticulum by Porc (step 1) and travels to the Golgi where it binds to Evi (step 2), facilitating its delivery to the apical plasma membrane (step 3). In model 1, Wnt and Evi dissociate on the plasma membrane. Wnt associates with Reggie-1/Flotillin-2 containing microdomains, and is internalized (step 4). In endosomal compartments, Wnt is loaded on lipoprotein particles by an unknown mechansim (step 5), and is released from the basolateral surface for long-range signalling (step 6). In model 2, Wnt and Evi are internalized together (step 4), and dissociate in endosomal compartments (step 5). There, Wnt is loaded on lipoprotein particles and released from the basolateral surface (step 6). In both models, Evi is recycled to the Golgi in a retromer-dependent manner (step 7). Note that, in both models, membrane-bound Wnt signals from the apical membrane to induce short-range targets, whereas the long-range concentration gradient forms on the basal surface. Evi, Evenness interrupted; Porc, Porcupine; Wls, Wntless.

Figure 3

Two-gradient model. Lipid-linked morphogens are secreted from the apical side of producing cells and accumulate on the surface due to their lipid anchor. There, they activate short-range target genes in adjacent cells (red). Transcytosis delivers them to the basolateral surface where they are secreted, possibly on lipoprotein particles. Diffusion of mobile morphogen complexes leads to the activation of long-range target genes (blue).

Michael Boutros & Kerstin Bartscherer