Editorial [ Hot Topic: Wnt Signaling (Guest Editor: Rashna D. Balsara) ]

Signaling pathways are ubiquitously present in organisms ranging from the simple metazoan Hydra to vertebrates. These pathways play a pivotal role in tightly regulating cell-cell communication that coordinates various biological activities, such as embryogenesis, development, tissue homeostasis and regeneration. Among the myriad signaling pathways elucidated, the Wnt signaling pathway has made a tremendous impact by not only increasing our understanding of development, but also towards understanding cellular perturbations that promote human degenerative diseases and cancer. Components of the Wnt signaling pathway have a rich evolutionary history, pre-dated about 650 million years ago. Investigators have identified several bilaterian Wnt gene subfamilies in cnidarians, drosophila, C. elegans and mammals indicating a common ancestral cluster of Wnt genes. There is extensive amount of conservation of the Wnt gene cluster making orthologous recognition easy, suggesting similar biological and biochemical activities. The Wnts are composed of a large family of highly conserved growth factors or ligands that bind to the Frizzled/LRP receptor complex, and relays their signals to the nucleus via several transduction intermediates. One of the most focused aspects of Wnt signaling has been the canonical pathway in which the cytoplasmic stabilization of β-catenin is controlled by a destruction complex, and its subsequent nuclear translocation and activity plays a central role. This well-defined model of Wnt signaling is also referred to as the β-catenin-dependent pathway. In the absence of Wnt, the destruction complex, which consists of Axin/Adenomatous Polyposis Coli (APC)/Glycogen Synthase Kinase-3 (GSK3) degrades β-catenin. Presence of Wnt ligands in association with the signaling intermediate Dishevelled blocks the activity of the destruction complex causing stabilization and accumulation of β-catenin. In the nucleus β-catenin interacts with the TCF/LEF-1 transcriptional activators resulting in the expression of specific Wnt target genes. However, the Wnt ligands are pleiotropic, and participate in signaling cascade events that are β-catenin-independent or the noncanonical pathway(s) that operates through a network of intermediates that are calcium-dependent or require GTPases. Depending on the interaction of Wnts with different surface receptors various cellular outcomes have been observed. Some atypical members of the receptor tyrosine kinase family, such as RYK can associate with Wnt, and elicit axon repulsion providing directional guidance to extending axons during mammalian central nervous system development. Another noncanonical pathway, now known as the planar cell polarity (PCP) pathway utilizes both Frizzled and Dishevelled, along with c-Jun N-terminal kinase, and a number of novel signaling molecules to regulate PCP. Paradoxically in this pathway the specific role of Wnt is not fully understood. Furthermore, the Wnt/PCP pathway via Frizzled7 and Dishevelled can regulate convergent extension (CE) movements in Xenopus embryos. Both the Wnt pathways have been presented in considerable details in the ensuing articles. Though in a given cell only a subset of Wnts can stimulate the canonical signaling pathway there is cross-talk between the two pathways, whereby the noncanonical pathway can directly antagonize the canonical pathway to regulate signals critical for vertebrate body axis determination, limb development, and possibly oncogenesis. Given the diverse functions of Wnt ligands it is not surprising Wnt function gone awry would lead to dire consequences in humans. Some of the disorders associated with dysfunctional Wnt signaling are cancers, bone density defects, and defects in retinal angiogenesis. In this special issue dedicated to Wnt signaling, all articles illustrate in detail the multifaceted functions potentiated by the Wnt ligands. The first article by Coombs and colleagues gives a lucid description on the history of Wnt signaling. It also introduces the reader on the role of Wnts in development, cancers, bone diseases and neuropsychiatric disorders. The article by Ewan and Dale focuses on cellular events triggered by ligand/receptor interaction with a view to exploit different players of this pathway for therapeutic purposes in oncogenic therapy. Aberrant Wnt signaling in colorectal cancer and associated genetic changes have been addressed by Qi and Zhu. They have also described structured therapeutic intervention at different levels of the Wnt pathway. Parmalee and Kitajewski have explained the role of Wnt through Frizzled4 on the newly discovered angiogenic factor Norrin with respect to retinal angiogenesis. The article by Katoh describes the role of Wnt signaling along with different signaling partners on a variety of stem cells, such as embryonic, neural, mesenchymal, hematopoietic and intestinal stem cells. Thus, enabling investigators to gain insights towards developing tissue engineering and regeneration technology.