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First published online 30 November 2006
doi: 10.1242/dev.02699

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The making of Wnt: new insights into Wnt maturation, sorting and secretion

Hubrecht Laboratory and Center for Biomedical Genetics, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.

View larger version (16K): [in this window] [in a new window]   Fig. 1. A schematic of mouse Wnt3A, Drosophila Wingless and the C. elegans Wnt protein EGL-20. Wnts do not contain specific domains, but harbour an average of 23 to 25 cysteines that are highly conserved between different species. One of the N-terminally located cysteines is palmitoylated by the O-acyltransferase Porcupine, which binds Wnt in the corresponding region (yellow box). Wnts also contain a number of potential N-glycosylation sites, the functions of which are unknown. The signal sequence is represented in blue.

View larger version (21K): [in this window] [in a new window]   Fig. 2. Wnts associate with lipoprotein particles. Wnts associate with lipoprotein particles that may partially counteract the palmitate-mediated affinity of Wnt for cell membranes, thereby allowing the spreading of the protein further along the morphogenetic field. (A) This association could occur extracellularly. (B) Alternatively, as suggested by the potential sorting of Wnt to endosomes, the association of Wnt with lipoprotein particles may occur within the Wnt-producing cells, after endocytosis and the endosomal targeting of extracellular lipoprotein particles. Only a low fraction of Wnt binds lipoprotein particles, suggesting that long-range-acting Wnt may use a specialized secretion route, whereas short-range-acting Wnt may enter the constitutive secretion pathway.

View larger version (26K): [in this window] [in a new window]   Fig. 3. Two models of the role of the retromer complex in Wnt maturation. (A) The retromer may directly or indirectly bind a putative Wnt cargo receptor in the TGN, directing the sorting of the Wnt-Wnt-cargo-receptor complex to the endosomes for association with lipoprotein particles (left panel). From the endosomes, the Wnt cargo receptors may either be recycled to the Golgi or degraded in the lysosomes. In the absence of retromer function, all Wnts enter the constitutive secretion pathway and exit the cells in their short-range-signalling form (right panel). (B) The retromer complex may retrieve the Wnt cargo receptors from the endosomes to the TGN, allowing the further cycling of Wnt molecules (left panel). In the absence of retromer function, the Wnt cargo receptors accumulate in the endosomes and are eventually degraded in the lysosomes. A shortage of Wnt cargo receptors in the TGN prevents the sorting of Wnts to the endosomes, resulting in constitutive secretion of short-range-acting Wnts (right panel).

View larger version (19K): [in this window] [in a new window]   Fig. 4. Production of a fully functional Wnt by Wnt-expressing cells. A schematic of some of the different models proposed in this review. The steps specific to the model where Wnt is secreted via the constitutive secretory pathway and associates with lipoprotein particles outside of the cells are in green. The steps specific to the specialized sorting route for endosomal association with lipoprotein particles and secretion of long-range-signalling Wnt are in red. The steps common to the two models are in black.