Epidemiological studies have revealed that the prenatal period is vulnerable to ASD
[71][72][73][74][75][76] and SCZ
[77][78][79][80][81][82][83][84][85]. Among the key signaling pathways regulating fetal brain development, Wnt proteins play indispensable roles in angiogenesis
[86][87][88][89][90], neurogenesis
[91][92][93][94][95][96][97][98], cell survival
[99][100][101][102], synaptogenesis
[103][104][105] and neurite outgrowth
[106][107]. The canonical pathway is well known to play a major role in neural development
[108]. WNT signaling is regulated by several key components of the canonical Wnt pathway, including β-catenin, whose level determines the activity of canonical Wnt signaling. Recently, mutations in β-catenin have been identified as a frequent cause of ID (OMIM #615075), known as CTNNB1 syndrome
[109][110][111][112][113][114], with some individuals also being diagnosed with ASD
[115][116][117][118][119]. CTNNB1 syndrome patients are characterized by low IQ, microcephaly and facial dysmorphism that cannot be attributed to a known clinical syndrome
[109][110][111][112][113][114]. A β-catenin conditional KO mouse specifically in PV interneurons showed that β-cat cKO mice have increased anxiety, impaired social interactions and elevated repetitive behaviors, which mimic some core symptoms of patients with ASD
[120]. In addition, several mouse models with KO of Wnt regulators have shown consistent ASD-like behavioral deficits, including APC
[121], DVL1
[122] and PTEN
[123][124][125][126]. These data provide compelling evidence that an abnormal Wnt pathway is involved in the development of mental illness.
The
BCL9 gene is located within the 1q21 region and encodes a nuclear retention factor for β-catenin, a critical part of the WNT signaling pathway
[127][128][129]. BCL9 is essential for activation of the Wnt signaling in adult myogenic progenitors and regulates muscle regeneration
[130]. To determine whether common variants in 1q21 can function as a candidate risk of SCZ, a large-scale GWAS comprising 5772 control and 4187 SCZ patients and 1135 patients with bipolar disorder was conducted in the Chinese Han population
[47]. Interestingly, multiple SNPs within the
BCL9 gene are significantly associated with SCZ. Consistently, other GWAS and integrative analyses suggest that
BCL9 is associated with negative symptoms in SCZ
[131][132] and is one of top risk genes in CNV
[133]. As disruption of the BCL9–β-catenin interaction inhibits Wnt activation
[134], which has been proposed as a therapeutic target for cancer
[135][136], it remains to be tested if increasing BCL9 levels or fine-tuning WNT signaling could reverse the deficits caused by 1q21 CNV. In addition, several components of the Wnt signaling show an association with SCZ
[137][138][139][140][141] and other psychiatric disorders
[115][142][143]. Among the genetic factors associated with schizophrenia, the DISC1
[144] gene is a genetic risk factor for major mental illness
[145][146][147][148][149]. DISC1 is a key regulator of NPC proliferation and mouse behavior through modulating the canonical Wnt signaling pathway
[150]. DISC1 regulates cortical NPC proliferation and neuronal differentiation via inhibition of GSK3β. Treatment with pharmacological inhibitors of GSK3β can completely ameliorate the DISC1 loss-of-function-induced progenitor proliferation defects and behavioral abnormalities, which illustrates the exciting opportunity to develop small-molecule modulators of the Wnt pathway as prototypical drug treatments for psychiatric diseases.