Wnt5a can both activate and repress Wnt/β-catenin signaling during mouse embryonic development

Abstract

Embryonic development is controlled by a small set of signal transduction pathways, with vastly different phenotypic outcomes depending on the time and place of their recruitment. How the same molecular machinery can elicit such specific and distinct responses, remains one of the outstanding questions in developmental biology. Part of the answer may lie in the high inherent genetic complexity of these signaling cascades, as observed for the Wnt-pathway. The mammalian genome encodes multiple Wnt proteins and receptors, each of which show dynamic and tightly controlled expression patterns in the embryo. Yet how these components interact in the context of the whole organism remains unknown. Here we report the generation of a novel, inducible transgenic mouse model that allows spatiotemporal control over the expression of Wnt5a, a protein implicated in many developmental processes and multiple Wnt-signaling responses. We show that ectopic Wnt5a expression from E10.5 onwards results in a variety of developmental defects, including loss of hair follicles and reduced bone formation in the skull. Moreover, we find that Wnt5a can have dual signaling activities during mouse embryonic development. Specifically, Wnt5a is capable of both inducing and repressing β-catenin/TCF signaling in vivo, depending on the time and site of expression and the receptors expressed by receiving cells. These experiments show for the first time that a single mammalian Wnt protein can have multiple signaling activities in vivo, thereby furthering our understanding of how signaling specificity is achieved in a complex developmental context.

Development of the lymphatic system: new questions and paradigms

“…Wnt5b has recently been established as both necessary and sufficient to promote lymphatic cell fate specification in zebrafish . Despite being classed as activator of the 'noncanonical' Wnt pathway, Wnt5 has also been shown to activate canonical downstream components in different contexts (Mikels and Nusse, 2006;van Amerongen et al, 2012). In the case of LEC specification, downstream activation of the β-catenin/TCF pathway was shown to be required for the induction of prox1 expression in prospective LEC progenitors.…”

Cell signaling in trophoblast-uterine communication

“…The term "Wnt" combines the Wg (Wingless) and Int1 genes, which were found to be homologous (Nusse et al, 1991). The Wnt pathway includes a large number of ligands and receptors (19 and 10 respectively), resulting in 190 different potential interactions, which can be enhanced or attenuated by additional co-receptors and co-activators with multiple signaling activities (van Amerongen et al, 2012). The Wnt signaling pathway is pleiotropic, as abnormalities in Wnt signaling are associated with cancers, osteoperosis, degenerative diseases and developmental disorders (Sonderegger et al, 2010).…”

Planar Cell Polarity Pathway in Kidney Development and Function

“…One possibility is that, during kidney development, Wnt5 and Wnt11 participate in both Wnt/ -catenin and PCP signaling. Indeed several Wnt molecules, including Wnt5a, were reported to act in both Wnt pathways [114] but the particular Wnt pathway activation seems to depend on unknown tissue-specific factors [115]. Another possibility is that the activities of the canonical Wnt and the PCP pathways are interdependent.…”