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Review
. 2010 May;38(2):148-53.
doi: 10.1016/j.nbd.2009.09.003. Epub 2009 Sep 16.

Wnt signaling in development and disease

Jennifer L Freese  1 , Darya Pino, Samuel J Pleasure
Affiliations
Review

Wnt signaling in development and disease

Jennifer L Freese et al. Neurobiol Dis. 2010 May.

Abstract

The Wnt signaling pathway is one of the central morphogenic signaling pathways regulating early vertebrate development. In recent years, it has become clear that the Wnt pathway also regulates many aspects of nervous system development from the patterning stage through the regulation of neural plasticity. In this review, we first present an overview of the components of the Wnt signaling pathway and then go on to discuss the literature describing the multitude of roles of Wnts in nervous system. In the latter portion of the review, we turn to the ways that defects in Wnt signaling lead to neurologic disease.

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Figures

Figure 1
Figure 1. A simplified representation of Wnt/β-catenin and β-catenin-independent signaling pathways
In the absence of Wnt ligand (far left), the “destruction complex” composed of the core proteins Axin, adenomatous polyposis coli (APC), and glycogen synthase kinase-3 (GSK3) rapidly phosphorylates (P) cytosolic β-catenin, targeting it for subsequent ubiquitination (Ub) and proteasome-mediated destruction. Binding of Wnt to Frizzled (Fzd) and low-density lipoprotein receptor-related protein 5/6 (LRP5/6) activates the cytosolic protein Dishevelled (DVL), leading to inhibition of the destruction complex. The resulting accumulated β-catenin can then translocate to the nucleus to activate Wnt-responsive target genes regulated by TCF and LEF family transcription factors, leading to various cellular effects. Activation of the small GTPases Rho and Rac can result in cytoskeletal rearrangements that affect cellular motility upon Wnt stimulation. Binding of Wnt isoforms to either Fzd or receptors such as receptor tyrosine kinase-like orphan receptor 2 (Ror2, a receptor for Wnt-5a), can trigger β-catenin-independent downstream signaling events, including the inhibition of Wnt/-catenin signaling. The mechanisms underlying β-catenin-independent Wnt signaling are not well defined, and may be largely determined by cellular context. The secreted inhibitor Dickkopf (DKK) can antagonize Wnt signaling by competitively binding to LRP5/6. Secreted Fzd-related proteins (SFRPs) and Wnt inhibitory factor (WIF) are thought to antagonize Wnt signaling by sequestering Wnt ligand in the extracellular space. (Figure originally published in (Chien et al., 2009).
See this image and copyright information in PMC

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