Abstract
Wnt signaling is a key pathway that helps organize development of the nervous system. It influences cell proliferation, cell fate, and cell migration in the developing nervous system, as well as axon guidance, dendrite development, and synapse formation. Given this wide range of roles, dysregulation of Wnt signaling could have any number of deleterious effects on neural development and thereby contribute in many different ways to the pathogenesis of neurodevelopmental disorders. Some major psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorders, are coming to be understood as subtle dysregulations of nervous system development, particularly of synapse formation and maintenance. This review will therefore touch on the importance of Wnt signaling to neurodevelopment generally, while focusing on accumulating evidence for a synaptic role of Wnt signaling. These observations will be discussed in the context of current understanding of the neurodevelopmental bases of major psychiatric diseases, spotlighting schizophrenia, bipolar disorder, and autism spectrum disorder. In short, this review will focus on the potential role of synapse formation and maintenance in major psychiatric disorders and summarize evidence that defective Wnt signaling could contribute to their pathogenesis via effects on these late neural differentiation processes.
Highlights
Wnt signaling is a key pathway that helps organize development of the nervous system
Wnt signaling is mediated by Wnt ligands binding to the Frizzled (Fzd) family of receptors, the co-receptors low density lipoprotein receptor-related protein 5 and 6 (LRP5/6), or alternatively the Ryk and Ror receptor tyrosine kinases (Komiya and Habas 2008)
Other genes linked to schizophrenia that can modulate Wnt signaling include Disrupted In SChizophrenia 1 (DISC1), a scaffold protein whose genetic locus is mutated in affected members of a family with a high incidence of schizophrenia (Millar et al 2000)
Summary
The Wnt family of signaling molecules are small secreted glycoproteins best known for their role as critical regulators of cell fate specification, cell proliferation, and cell migration during development. There are 19 Wnt ligands made from different genetic loci in humans and a similar number in other mammals. Wnt signaling is mediated by Wnt ligands binding to the Frizzled (Fzd) family of receptors, the co-receptors low density lipoprotein receptor-related protein 5 and 6 (LRP5/6), or alternatively the Ryk and Ror receptor tyrosine kinases (Komiya and Habas 2008). Wnts can initiate several signaling pathways through activation of these different receptor types and complexes (Fig. 1). The so-called canonical Wnt/β-catenin signaling pathway involves Wnt binding to Fzd and LRP5/6, followed by Fzd binding to the scaffold protein Disheveled (dsh in fly, Dvl in vertebrates). Dvl binds and destabilizes the β-catenin destruction complex, a group of proteins including glycogen synthase kinase 3 (GSK3) and the scaffold proteins axin and adenomatous polyposis coli (APC), among others. The constitutively functioning destruction complex binds β-catenin and targets it for poly-ubiquitination and
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