The Wnt signaling pathway is an ancient and evolutionarily conserved pathway that regulates crucial aspects of cell fate determination, cell migration, cell polarity, neural patterning and organogenesis during embryonic development. The Wnts are secreted glycoproteins and comprise a large family of nineteen proteins in humans hinting to a daunting complexity of signaling regulation, function and biological output.

Wnts are secreted signalling molecules critical to many developmental processes such as organogenesis and their aberrant activity is associated with a number of disorders including . The mechanisms through which Wnt ligands mediate these diverse functions had remained elusive until the discovery of other Wnt pathway components in the 1990s, including the Frizzled (Fzd) family of transmembrane receptors, downstream effectors like Disheveled (Dvl), Axin/conductin, (β-catenin, and the T cell factor (TCF) family of transcription factors. The turn of the century led to the discovery of low-density-lipoprotein receptor (LDLR)-related proteins, Lrp5 and Lrp6, as novel members of the Wnt signaling cascade. The discovery of these components was critical to the establishment of a basic framework for the Wnt signaling cascade, and aided in providing a mechanistic insight into how Wnt ligands transduce signals across the plasma membrane, through the cytoplasm, and finally into the nucleus where Wnt-dependent gene transcription is regulated.

In mammals, 19 different Wnts and 10 WNT receptors (Frizzleds) have been discovered thus far. Dependent on the context of the cell receiving a Wnt signal, Wnt molecules can be categorized as canonical or non-canonical. When a canonical Wnt binds its cognate Frizzled receptor with lipoprotein receptor-related protein (LRP)5/6 co-receptor, the effector molecule β-catenin is stabilized in the cytosol and translocates to the nucleus where it binds T-cell factor (TCF)/lymphoid enhancer-binding factor 1 (LEF1) to activate transcription of proliferative genes, such as c-myc. Wnts can also activate β-catenin-independent (non-canonical) pathways that direct the asymmetric localization of intracellular proteins involved in determining cell shape, movement, and cytokinesis. Such processes involve numerous effector molecules whose functions remain less well understood, particularly in kidney development.

Numerous studies have highlighted the importance of the small GTPases RhoA, Rac and Cdc42 in non-canonical Wnt signaling. In Xenopus embryos, Wnt11 activation of RhoA via Dvl and Dishevelled-associated activator of morphogenesis (Daaml) regulates the cytoskeleton and gastrulation. In addition to Rho, Wnt activation of Rac and JNK in association with Dvl appears to be important in gastrulation, particularly in the convergent extension process in which the anterior-posterior axis elongates and the mediolateral axis contracts in Xenopus and zebrafish embryonic development. Activation of Cdc42 has also been implicated in Wnt regulation of convergent extension. Rac and RhoA each play a role in Wnt driven directional migration of neural crest cells, while RhoA is required for Wnt mediated neurite retraction. Cdc42, through activation of the Par6/aPKC complex is important for noncanonical Wnt mediated microtubule reorganization and generation of cell polarization during migration. In addition to modulating Wnt signaling in development and in the normal cell, GTPases have also been shown to mediate effects of non-canonical Wnt signaling in cancer. Dvl-Daam-Rho, and Dvl- Rac1 interactions are important to facilitate Wnt5a mediated breast cancer cell migration, and Cdc42 in Wnt5b mediated migration of oral cancer cells. Numerous other roles for GTPases in Wnt signaling have been identified and will likely continue to be uncovered with further studies.

The Wnt/Calcium pathway is somewhat controversial and has mixed support within the field. Wnt stimulation of this pathway promotes intracellular calcium release from calcium stores, through second messengers inositol triphosphate (IP3) and diacylglycerol (DAG), which then activate calmodulindependent protein kinase II (CaMKII) activity, calcineurin and nuclear factor associated with T cells (NFAT) mediated transcription. This pathway was identified during Wnt mediated gastrulation, and has also been implicated in Wnt in cancer and axon guidance. Wnt/calcium signaling induces Dvl/ NFAT complex formation which may repress β-catenin mediated transcription.


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