The complex world of WNT receptor signalling.

30 years after the identification of WNTs, their signal transduction has become increasingly complex, with the discovery of more than 15 receptors and co-receptors in seven protein families. The recent discovery of three receptor classes for the R-spondin family of WNT agonists further adds to this complexity. What emerges is an intricate network of receptors that form higher-order ligand-receptor complexes routing downstream signalling. These are regulated both extracellularly by agonists such as R-spondin and intracellularly by post-translational modifications such as phosphorylation, proteolytic processing and endocytosis.

The role of Wnt signaling in male reproductive physiology and pathology.

Accumulating evidence has shown that Wnt signaling is deeply involved in male reproductive physiology, and malfunction of the signal path can cause pathological changes in genital organs and sperm cells. These abnormalities are diverse in manifestation and have been constantly found in the knockout models of Wnt studies. Nevertheless, most of the research solely focused on a certain factor in the Wnt pathway, and there are few reports on the overall relation between Wnt signals and male reproductive physiology. In our review, Wnt findings relating to the reproductive system were sought and summarized in terms of Wnt ligands, Wnt receptors, Wnt intracellular signals and Wnt regulators. By sorting out and integrating relevant functions, as well as underlining the controversies among different reports, our review aims to offer an overview of Wnt signaling in male reproductive physiology and pathology for further mechanistic studies.

Wnt4 signaling mediates protective effects of melatonin on new bone formation in an inflammatory environment.

Growing evidence shows that the inhibitory effect of inflammatory cytokines on new bone formation by osteogenic precursor cells is a critical cause of net bone-density reduction. Melatonin has been proven to be a potential therapeutic candidate for osteoporosis. However, whether it is capable of antagonizing the suppressing effect of inflammatory cytokines on osteogenic precursor cells is so far elusive. In this study, using the cell culture system of human bone marrow stromal cells and MC3T3-E1 preosteoblasts, we recorded the following vital observations that provided insights of melatonin-induced bone formation: 1) melatonin induced bone formation in both normal and inflammatory conditions; 2) Wnt4 was essential for melatonin-induced bone formation in inflammatory stimulation; 3) melatonin- and Wnt4-induced bone formation occurred via activation of ß-catenin and p38-JNK MAPK pathways by interaction with a distinct frizzled LDL receptor-related protein complex; 4) melatonin suppressed the inhibitory effect of NF-κB on osteogenesis in a Wnt4-dependent manner; and 5) melatonin induced Wnt4 expression through the ERK1/2-Pax2-Egr1 pathway. In summary, we showed a novel mechanism of melatonin-induced bone formation in an inflammatory environment. Melatonin-induced Wnt4 expression is essential for its osteoinductive effect and the inhibitory effect of NF-κB on bone formation. Our novel findings may provide useful information for its potential translational application.-Li, X., Li, Z., Wang, J., Li, Z., Cui, H., Dai, G., Chen, S., Zhang, M., Zheng, Z., Zhan, Z., Liu, H. Wnt4 signaling mediates protective effects of melatonin on new bone formation in an inflammatory environment.

Wnt signaling mediates pathological vascular growth in proliferative retinopathy.

BACKGROUND: Ischemic proliferative retinopathy, characterized by pathological retinal neovascularization, is a major cause of blindness in working-age adults and children. Defining the molecular pathways distinguishing pathological neovascularization from normal vessels is critical to controlling these blinding diseases with targeted therapy. Because mutations in Wnt signaling cause defective retinal vasculature in humans with some characteristics of the pathological vessels in retinopathy, we investigated the potential role of Wnt signaling in pathological retinal vascular growth in proliferative retinopathy. METHODS AND RESULTS: In this study, we show that Wnt receptors (Frizzled4 and low-density lipoprotein receptor-related protein5 [Lrp5]) and activity are significantly increased in pathological neovascularization in a mouse model of oxygen-induced proliferative retinopathy. Loss of Wnt coreceptor Lrp5 and downstream signaling molecule dishevelled2 significantly decreases the formation of pathological retinal neovascularization in retinopathy. Loss of Lrp5 also affects retinal angiogenesis during development and formation of the blood-retinal barrier, which is linked to significant downregulation of tight junction protein claudin5 in Lrp5(-/-) vessels. Blocking claudin5 significantly suppresses Wnt pathway-driven endothelial cell sprouting in vitro and developmental and pathological vascular growth in retinopathy in vivo. CONCLUSIONS: These results demonstrate an important role of Wnt signaling in pathological vascular development in retinopathy and show a novel function of Cln5 in promoting angiogenesis.

Wnt signaling in the vertebrate central nervous system: from axon guidance to synaptic function.

Regulation of cell signaling by Wnt proteins is critical for the formation of neuronal circuits. Wnts modulate axon pathfinding, dendritic development, and synaptic assembly. Through different receptors, Wnts activate diverse signaling pathways that lead to local changes on the cytoskeleton or global cellular changes involving nuclear function. Recently, a link between neuronal activity, essential for the formation and refinement of neuronal connections, and Wnt signaling has been uncovered. Indeed, neuronal activity regulates the release of Wnt and the localization of their receptors. Wnts mediate synaptic structural changes induced by neuronal activity or experience. New emerging evidence suggests that dysfunction in Wnt signaling contributes to neurological disorders. In this article, the attention is focused on the function of Wnt signaling in the formation of neuronal circuits in the vertebrate central nervous system.

Alternative Wnt pathways and receptors.

In addition to activating ß-catenin/TCF transcriptional complexes, Wnt proteins can elicit a variety of other responses. These are often lumped together under the denominator "alternative" or "non-canonical" Wnt signaling, but they likely comprise distinct signaling events. In this article, I discuss how the use of different ligand and receptor combinations is thought to give rise to these alternative Wnt-signaling responses. Although many of the biochemical details remain to be resolved, it is evident that alternative Wnt signaling plays important roles in regulating tissue morphogenesis during embryonic development.

Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders.

The renin-angiotensin system and Wnt/frizzled receptor signaling pathways are important in the development of essential organs, and their aberrant activation results in cardiovascular and renal pathologies. The (pro)renin receptor ((P)RR)-bound (pro)renin is enzymatically active generating angiotensin-II and activating mitogen-activated protein kinases, leading to cell proliferation and to upregulation of profibrotic genes expression, resulting in end-organ damage. The (P)RR does more than bind to (pro)renin, because it is functionally linked to the vacuolar-H(+)-ATPase (v-H(+)-ATPase) that regulates pH of cellular and intracellular vesicles, and to Wnt signaling. This signaling pathway is essential for cell survival, embryonic development and has had a role in various disease states as evidenced by mutation or genetic ablation of the (P)RR gene. This suggests two types of functions of (P)RRs, first one as a receptor for (pro)renin and second one as an accessory subunit of the v-H(+)-ATPase and a cofactor of the Wnt/Fz receptor complex. This review will discuss both of these functions of (P)RRs thereby giving new perspectives as to the roles of (P)RRs in cardiovascular and renal pathologies.