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

Abstract

Wnt glycoproteins are extracellular ligands that can be found in many species, ranging from the sea anemone Nematostella vectensis to human (Kusserow et al., 2005). Wnts act as morphogens and control the patterning of the developing embryo by triggering concentration-dependent responses in cells located at a distance from the signal-sending domain (Neumann and Cohen, 1997; Strigini and Cohen, 2000; Zecca et al., 1996). During animal development, Wnt ligands regulate several key processes, such as cell proliferation, cell migration and cell differentiation (Cadigan and Nusse, 1997; Moon et al., 2002; Wodarz and Nusse, 1998). Furthermore, deregulation of the Wnt signalling pathway has been implicated in many pathological disorders, including colon cancer (Bienz and Clevers, 2000; Logan and Nusse, 2004). The intracellular mechanisms that transduce the Wnt signal downstream of its receptors and modulate the expression of its target genes have been extensively studied, and will not be discussed here (for review, see Cadigan and Liu, 2006; Cadigan and Nusse, 1997; He et al., 2004; Moon et al., 2002; van Es et al., 2003) (also see the Wnt Homepage http://www.stanford.edu/~rnusse/wntwindow.html). However, little is known about the different steps that control the synthesis and secretion of a functional Wnt protein, and which ensure its delivery to the responding cells along the morphogenetic field. In this review, we focus on Wnt-producing cells and discuss the mechanisms that lead to the production of a fully active Wnt. All known aspects of Wnt maturation will be addressed: from its post-translational modification in the endoplasmic reticulum (ER) to its sorting within the expressing cells and, finally, to its secretion as a long-range-acting protein. Although the influence of Wnt properties on the formation of an extracellular concentration gradient will be mentioned, the multiple mechanisms that regulate the spreading of Wnt will not be presented here. For overviews of these processes, the reader is referred to other reviews (Cadigan, 2002; Eaton, 2006; Strigini and Cohen, 2000; Vincent and Dubois, 2002).