A review of the evidence for the canonical Wnt pathway in autism spectrum disorders

Abstract

Microdeletion and microduplication copy number variations are found in patients with autism spectrum disorder and in a number of cases they include genes that are involved in the canonical Wnt signaling pathway (for example, FZD9, BCL9 or CDH8). Association studies investigating WNT2, DISC1, MET, DOCK4 or AHI1 also provide evidence that the canonical Wnt pathway might be affected in autism. Prenatal medication with sodium-valproate or antidepressant drugs increases autism risk. In animal studies, it has been found that these medications promote Wnt signaling, including among others an increase in Wnt2 gene expression. Notably, the available genetic information indicates that not only canonical Wnt pathway activation, but also inhibition seems to increase autism risk. The canonical Wnt pathway plays a role in dendrite growth and suboptimal activity negatively affects the dendritic arbor. In principle, this provides a logical explanation as to why both hypo- and hyperactivity may generate a similar set of behavioral and cognitive symptoms. However, without a validated biomarker to stratify for deviant canonical Wnt pathway activity, it is probably too dangerous to treat patients with compounds that modify pathway activity.

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

“…The same study also provided evidence supporting a “goldilocks principle” for Wnt signaling in these processes at the dendritic spine and synapse, showing that either too much or too little signal pathway activation is similarly deleterious [343]. This is consistent with the established importance of Wnt pathway dosage and the role of Wnts as morphogens in other developmental contexts [75,121,197,346,347,348,349]. Together, the recent work in animals and hIPSCs underscores how experimental model systems in which genetic, signaling, neurodevelopmental, circuit, and behavioral phenotypes are simultaneously characterized and correlated can be used to test hypotheses and potentially to develop and test novel psychopharmaceuticals that modulate Wnt/β-catenin signaling.…”

The Atypical Guanine Nucleotide Exchange Factor Dock4 Regulates Neurite Differentiation through Modulation of Rac1 GTPase and Actin Dynamics

“…Given that the DHR1 domain of Dock4 is capable of binding to phosphatidylinositol trisphosphate (3,4,5), a lipid product of PI3K (30), it is possible that Dock4 is recruited and activated by the increased production of phosphatidylinositol trisphosphate resulting from RA-dependent PI3K activation. On the other hand, Dock4 is involved in signaling pathways mediated by several extracellular or upstream factors, including Wnts and RhoG, which are important factors for neuronal development (21,23,43). Thus, it will be important to examine whether transcription or activity of these molecules are regulated by RA.…”

WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4

“…Similarly, it is unclear whether WNT pathway overactivation, or underactivation, or both, occur in autism spectrum disorders [23]. However, overexpression of TCF4 in mice causes cognitive and sensorimotor gating impairments [16].…”

“…Furthermore, chromatin remodeling complexes known to interact with β-catenin can bind to a TCF4 promoter in cancer cells [22]. Importantly, WNT pathway dysregulation may be a component of neuropsychiatric disease pathology, as genetic variation at WNT signaling gene loci has been associated with both schizophrenia and neurodevelopmental disorders [9,23]. However, WNT pathway regulation of TCF4 expression in human neural progenitor cells (NPCs) and postmitotic neurons has not yet been studied and thus represents a critical question to address in order to delineate mechanisms of TCF4 regulation in the CNS.…”