Synaptic Wnt signaling—a contributor to major psychiatric disorders?

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

Dact1 presomitic mesoderm expression oscillates in phase with Axin2 in the somitogenesis clock of mice.

During segmentation (somitogenesis) in vertebrate embryos, somites form in a rostral-to-caudal sequence according to a species-specific rhythm called the somitogenesis clock. The expression of genes participating in somitogenesis oscillates in the presomitic mesoderm (PSM) in time with this clock. We previously reported that the Dact1 gene (aka Dpr1/Frd1/ThyEx3), which encodes a Dishevelled-binding intracellular regulator of Wnt signaling, is prominently expressed in the PSM as well as in a caudal-rostral gradient across the somites of mouse embryos. This observation led us to examine whether Dact1 expression oscillates in the PSM. We have found that Dact1 PSM expression does indeed oscillate in time with the somitogenesis clock. Consistent with its known signaling functions and with the "clock and wavefront" model of signal regulation during somitogenesis, the oscillation of Dact1 occurs in phase with the Wnt signaling component Axin2, and out of phase with the Notch signaling component Lfng

Dact1 presomitic mesoderm expression oscillates in phase with Axin2 in the somitogenesis clock of mice.

During segmentation (somitogenesis) in vertebrate embryos, somites form in a rostral-to-caudal sequence according to a species-specific rhythm called the somitogenesis clock. The expression of genes participating in somitogenesis oscillates in the presomitic mesoderm (PSM) in time with this clock. We previously reported that the Dact1 gene (aka Dpr1/Frd1/ThyEx3), which encodes a Dishevelled-binding intracellular regulator of Wnt signaling, is prominently expressed in the PSM as well as in a caudal-rostral gradient across the somites of mouse embryos. This observation led us to examine whether Dact1 expression oscillates in the PSM. We have found that Dact1 PSM expression does indeed oscillate in time with the somitogenesis clock. Consistent with its known signaling functions and with the "clock and wavefront" model of signal regulation during somitogenesis, the oscillation of Dact1 occurs in phase with the Wnt signaling component Axin2, and out of phase with the Notch signaling component Lfng

Three Dact gene family members are expressed during embryonic development and in the adult brains of mice

Members of the Dact protein family initially were identified through binding to Dishevelled (Dvl), a cytoplasmic protein central to Wnt signaling. During mouse development, Dact1 is detected in the presomitic mesoderm and somites during segmentation, in the limb bud mesenchyme and other mesoderm-derived tissues, and in the central nervous system (CNS). Dact2 expression is most prominent during organogenesis of the thymus, kidneys, and salivary glands, with much lower levels in the somites and in the developing CNS. Dact3, not previously described in any organism, is expressed in the ventral region of maturing somites, limb bud and branchial arch mesenchyme, and in the embryonic CNS; of the three paralogs, it is the most highly expressed in the adult cerebral cortex. These data are consistent with studies in other vertebrates showing that Dact paralogs have distinct signaling and developmental roles and suggest they may differentially contribute to postnatal brain physiology

Posterior malformations in Dact1 mutant mice arise through misregulated Vangl2 at the primitive streak

Mice homozygous for mutations in Dact1 (Dpr/Frodo) phenocopy human malformations involving the spine, genitourinary system, and distal digestive tract. We trace this phenotype to disrupted germ layer morphogenesis at the primitive streak (PS). Remarkably, heterozygous mutation of Vangl2, a transmembrane component of the Planar Cell Polarity (PCP) pathway, rescues recessive Dact1 phenotypes, whereas loss of Dact1 reciprocally rescues semidominant Vangl2 phenotypes. We show that Dact1, an intracellular protein, forms a complex with Vangl2. In Dact1 mutants, Vangl2 is increased at the PS where cells ordinarily undergo an epithelial-mesenchymal transition. This is associated with abnormal E-cadherin distribution and changes in biochemical measures of the PCP pathway. We conclude that Dact1 contributes to morphogenesis at the PS by regulating Vangl2 upstream of cell adhesion and the PCP pathway