Furkan Candar1, Oytun Erbaş1,2

1Institute of Experimental Medicine, Gebze-Kocaeli, Turkey
2Department of Physiology, Medical Faculty of Demiroğlu Bilim University, Istanbul, Turkey

Keywords: Autism, cancer, Rett syndrome, tumor, WNT/β‐catenin


The WNT family is a group of signaling molecules that have been shown to control various developmental processes, including cell specification, proliferation, polarity, and cell migration. Dysregulation of WNT signaling plays a role in developmental defects and tumor formation. The importance of WNT signaling in development and clinical pathologies has been emphasized by studies examining various aspects of WNT signaling. There is data suggesting that WNT signaling hyperactivation leads to the pathogenesis of autism spectrum disorder. In this review, the molecular mechanism of WNT/β‐catenin signal transduction as well as the relationship of WNT/β‐catenin signaling dysregulation with tumor formation and autism are discussed.


WNT signaling is one of the main mechanisms that determine cell proliferation, cell polarity, and cellular outcome during embryonic development and tissue homeostasis.[1] Mutations in the WNT pathway are often linked to developmental defects, cancer, and other diseases. Critical to these processes and the most studied WNT pathway is the canonical WNT signal, which controls gene expression programs that play a key role in development and also regulates the amount of the transcriptional co-activator beta (β)-catenin.[2]

Beta-catenin was first defined as a protein located in the cell membrane that plays a role in cell adhesion. By acting as a bridge between the cytoplasmic portion of E-cadherin and alpha (α)-actin, one of the cytoskeletal elements in the cytosol, it is a molecule which plays a role in cell-cell interactions.[3] Determining of the homology of the β-catenin protein with the Armadillo protein (Arm) found in Drosophila revealed that it also functions as a transcription factor.[4,5] The β-catenin protein contains binding sites in its structure that bind to many molecules such as adenomatous polyposis coli (APC), Axin, and T-cell factor/lymphoid enhancer factor 1 (TCF/LEF-1).[6,7] By identifying the interacting biomolecules, it was revealed that the β-catenin protein plays important roles not only in cell adhesion but also in the WNT/β-catenin signaling pathway.

Another remarkable region of the β-catenin protein structure is the phosphorylation regions located at the N-terminal end which are significant for its stabilization.[8,9] The WNT/β-catenin signaling pathway regulates the level of β-catenin in the cytoplasm and nucleus via the destruction complex in the cytosol. When the signaling pathway is inactive, phosphorylation of regions rich in serine amino acids found in the structure of the β-catenin protein acts as a marker for the degradation of the β-catenin protein. While there is no mutation in the biomolecules involved in the signaling pathway, the b-catenin left over from destruction is found in the cell membrane to function in cell-cell adhesions.[10] When the signaling pathway is active, the destructive complex disintegrates, the β-catenin cannot be phosphorylated and the level of β-catenin in the cytoplasm increases. When any mutation occurs in the CTNNB-1 (Catenin Beta 1) gene, which encodes the β-catenin protein, especially those which prevent the protein from being phosphorylated at the N-terminal, various diseases and many types of cancer formation may occur.[11,12]

The WNT signal controls and regulates anteroposterior axis formation and neural differentiation in the brain during early vertebrate development.[13] Therefore, any disruption in WNT signaling can trigger disorders related to the structure and function of the central nervous system.[14,15]

Irregularity of the WNT signal has been reported in various psychiatric disorders such as Autism Spectrum Disorder (ASD), bipolar disorder, schizophrenia, as well as mental disability.[14,16]

WNT Signaling Pathway Mechanis

Three types of WNT signaling pathways have been identified: WNT/β-catenin (canonical), WNT/Ca+2 (non-canonical), and WNT/Planar Cell Polarity (PCP) (non-canonical).[17]

In the WNT/β-catenin signaling pathway, intracellular signalization starts the Wnt ligand (WNT1, WNT2, WNT3, WNT3a, WNT7a, WNT7b, WNT8a, WNT8b, WNT10b, or WNT16) binding to the Frizzled (Fz) receptor and the Fz coreceptor defined as low-density lipoprotein receptor-related protein 5/6 (LRP5/6) protein. Thus, the ternary structure (Fz-WNT-LRP5/6) required to initiate the WNT signaling mechanism is formed.[18] After this binding, the signal first passes to the cytoplasm and DVL (disheveled) phosphorylation is activated. Then, this phosphorylation disintegrates the destruction complex, which is comprised of Axin, APC, CK1 (casein kinase 1), GSK-3 (glycogensynthase kinase 3), which provides stabilization and nuclear translocation of β-catenin. β-catenin enters the nucleus and binds to TCF/LEF which are members of the transcription factor family, and with the help of coactivators p300 and CBP (CREB-binding protein), allowing the transcription of several WNT target genes that enable cell proliferation.[19] In the absence of the WNT ligand, the cytoplasmic β-catenin is marked for degradation by the destruction complex, which occurs by phosphorylation of serine and threonine residues in the N-terminal of β-catenin by CK1 and GSK3 components.[20]

The other two non-canonical pathways are associated with differentiation, cell polarity, and migration. In the non-canonical WNT/PCP pathway, when WNT ligands bind to the Fz receptors, GTPases such as RhoA (Ras homolog family member A), RAC (Ras-related C3 botulinum toxin substrate), and Cdc42 (cell division control protein 42) are activated.[21] The PCP pathway affects the cytoskeleton and stimulates transcriptional activation of target genes responsible for cell adhesion.[22] In the non-canonical WNT/Ca+2 pathway, when WNT ligands bind to Fz receptors or alternative receptors (Ryk or ROR), cell migration and inhibition of the WNT/β-catenin pathway occurs through intracellular Ca+2 influx and activation of calmodulin kinase II (CaMK2), Jun kinase (JNK), and PKC.[23]

Aside from secreted WNT, R-spondin ligand family members have been discovered as positive effectors of WNT signaling.[24-26] R-spondins bind to the leucine-rich repeat-containing G-protein coupled receptor (LGR) 4-6.[27] When R-spondin does not bind, the two homologous E3 ubiquitin ligases ZNRF3/RNF43 targets the Frizzled (Fzd) receptor for lysosomal degradation.[28] The binding of R-spondins to the G-protein coupled receptor 4-6 inhibits the activity of ZNRF3/RNF43 and leads to the accumulation of Fzd receptors on the cell surface.[26,29] The interaction of ZNRF3 and RNF43 with the Fzd receptor has been found to be promoted by DVL.[30]

Relationship of Cancer Types to WNT/β–Catenin Signaling Pathway

Abnormal WNT signaling often leads to high β-catenin levels in the nucleus, and this consequence is associated with various types of cancer. One of the malignancies most strongly associated with abnormal WNT signaling is colorectal cancer.[31]

The WNT pathway is up-regulated in colorectal cancers. WNT, which is normally activated in the crypts of intestinal glands, plays a critical role in cell repair and maintenance of stem cell functions. The primary mechanism of WNT pathway activation is the deactivation of APC, which acts as a negative regulator. Deactivation of the APC protein eliminates destruction complexmediated ubiquitination of β-catenin and activates WNT/β-catenin signaling.[32]

Aside from APC, mutations of the R-spondin/Lgr5/Rnf43 module have been identified as driving forces of WNT-dependent tumor growth, and deleterious RNF43 mutations have been identified in approximately 19% of colorectal cancer cases. These mentioned mutations are not independent of APC mutations. In addition, excessive expression of R-spondin-3 mutations and fusion proteins have been demonstrated in 10% of colorectal cancer cases.[33]

Chromosomal instability is common in colorectal cancer and is associated with poor prognosis. Dysfunction of WNT pathway components, particularly APC, has been linked to chromosomal instability through multiple mechanisms. The direct interactions of APC with the cytoskeleton and the transcriptional WNT response via the β-catenin pathway are among the routes to chromosomal instability.[34,35]

Unlike colorectal cancer, mutations of key WNT pathway components are rare in pancreatic ductal adenocarcinoma (PDAC). However, aberrant nuclear localization of β-catenin is frequently observed.[36] Results from mouse models indicate that WNT signaling promotes tumor formation when activated at different tumor stages.[37]

Recent studies have shown that PDAC cell lines that carry an RNF43 mutation are particularly susceptible to treatment with porcupine (PORCN) inhibitor LGK974.[38] PORCN is a member of the MBOAT (membrane associated O-acyl transferase) family and is responsible for the lipid modification and secretion of WNT.[39] Response to treatment with LGK974 indicates that PDAC is based on WNT ligand stimulation.[38] Furthermore, in addition to induction of the WNT antagonist DKK1, treatment with anti-Fzd antibody OMP18R5 delays PDAC formation.[40,41]

WNT signaling is also activated in cholangiocarcinoma, however, genomic changes of major WNT pathway components, with the exception of RNF43, are rare.[41,42] Pharmacological inhibition of the WNT signal at both β-catenin and WNT secretion levels decreased the proliferation of cholangiocarcinoma cells in a studied mouse model.[43] Moreover, secreted WNT signal inhibitors such as SFRP2 are often silenced by hypermethylation in cholangiocarcinoma.[44,45]

In recent years, knowledge of the role of the WNT signaling in hematopoiesis and leukemia has increased.[46] Normal hematopoietic stem cells (HSC) depend on a sensitive WNT signal level for long-term maintenance, whereas WNT activity is significantly increased in most leukemias.[47]

Beta-catenin is considered necessary for the progression of leukemia-initiating cells (LIC) from pre-LIC to LIC state and for the self-renewal of the LIC.[48,49]

The most common leukemia in childhood is acute lymphoblastic leukemia. It has been observed that canonical WNT signaling is a driving force during tumorigenesis of the specific T-cell acute lymphoblastic (T-ALL).[50]

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in Western countries. Canonical WNT signaling is active in CLL cells and its inhibition increases in vitro apoptosis. In a portion of studied cases, alongside frequent silencing of WNT inhibiting factors such as DKK1/2, somatic mutations in genes related to the WNT pathway were found in a fraction of studied patients. While knockdown of mutated WNT pathway members reduced cell viability in CLL cells carrying the targeted WNT pathway alteration, those without WNT pathway mutations remained unaffected. These findings demonstrate that a subset of CLL is dependent on active WNT signaling for survival.[51]

WNT signaling is activated in over half of breast cancer cases and is associated with reduced overall survival.[52] The role of canonical WNT signaling in the development and progression of triple negative breast cancer has been studied.[53] Furthermore, high levels of nuclear β-catenin have been found in other breast cancer subtypes.[54] Although only a small fraction of tumors harbors somatic mutations of key regulators of this pathway, such as β-catenin, canonical WNT ligands and receptors are often overexpressed in breast cancers.[55,56] The secreted antagonists are silenced.[57] In addition, overexpression of R-spondin-2 has also been shown to induce breast tumors in mouse models.[58]

In a significant portion of prostate tumors, increased β-catenin levels are seen in the cytoplasm or nucleus either as a result of gene mutations or as a result of non-genomic changes in the expression of inhibitors and activators of the WNT signal.[59]

WTX, a tumor suppressor protein involved in destruction complex function, is mutated in some cases of Wilms' tumor, a form of pediatric kidney cancer.[60] WTX occurs in the destruction complex in which β-catenin promotes degradation, making its tumor suppressor properties equivalent to those of APC and Axin.[61]

WNT signaling has an important place in neural differentiation during early vertebrate development.[13] In contrast, the abnormal WNT signal in neural stem cells (NSCs) stimulates malignant transformation and initiates the formation of brain tumors.[62]

The DNA repair gene platelet activating factor (PAF) is specifically overexpressed in colon cancer and intestinal stem cells. PAF mechanically strengthens WNT signaling by incorporating histone methyltransferase EZH2 into the TCF transcriptional complex.[63]

There is evidence indicating that WNT signaling contributes to the growth of cancer cells or cancer stem cells in a paracrine mode, and that metastatic tumor cells carry the activating properties of WNT signaling.[64,65]


Studies have shown that mutations of genes related to the WNT pathway contribute to autism spectrum disorder (ASD).[14]

WNT1 mutation, found in some ASD patients, has a higher capacity to activate WNT/β-catenin signaling than wild-type WNT1.[66] In particular, the increase in WNT3 expression, which normally plays a role in gastrulation and hippocampal neurogenesis in the prefrontal cortex of ASD patients,[67] suggests that hyperactivation of the WNT signal leads to ASD pathogenesis.[68,69] WNT2 has been shown to be essential for cortical dendrite growth and dendritic arborization. Its expression is regulated by brain-derived neurotrophic factor (BDNF), while its overexpression leads to dendritic spines resulting in neurodevelopmental and neurodegenerative disorders.[70] WNT2 has been associated with susceptibility to autism, WNT2 gene polymorphisms have been reported to cause speech delay inherent to autism.[71,72]

Human APC inactivating gene mutations have been associated with ASD.[73] Compared to wild-type offspring, conditional knockout (cKO) APC mice exhibit learning and memory impairments, and autistic-like behaviors. β-catenin and canonical WNT target gene expressions (Dkk1, Sp5, Neurog1, Syn2) are increased in APC-cKO forebrain neurons.[1] Furthermore, the lysates from the hippocampal, cortical, and striatal regions of Apc-cKO mice showed higher β-catenin levels compared to those of control mice.[74] These results also indicate that hyperactivation of WNT/β-catenin signaling may be a cause of ASD.

Loss of function mutations in de novo β-catenin (CTNNB1) have been reported in people with ASD mental disability, microcephaly, motor delay, and speech impairment. Conditional ablation of β-catenin in parvalbumin interneurons in mice leads to impaired object recognition and social interactions, as well as elevated repetitive behaviors, which are core symptoms of ASD patients, and surprisingly, they showed enhanced spatial memory.[66] To determine the effect of CTNNB1 conditional knockout in overall neuronal activity, it was determined that c-Fos was significantly reduced in the cortex, but not in the dentate gyrus and the amygdala. The findings revealed a cell type-specific role of CTNNB1 gene in regulation of cognitive and autistic-like behaviors.[75]

TCF7L2 is one of the TCF/LEF1 transcription factors in the canonical WNT/β-catenin signaling pathway and is associated with type II diabetes in humans.[76] De novo loss of function mutations of TCF7L2 have been found in ASD patients.[77,78]

Whole-genome and whole-exome sequencing studies have identified mutations of the ANK3 gene in ASD patients.[79] The ankyrin G protein encoded by ANK3 functions as a scaffold protein.[80] Ankyrin-G facilitates cell-cell contact by binding E-cadherin in a protected region different from β-catenin and localizes β-catenin to the cell adhesion site in early embryos and cultured epithelial cells. Ankyrin-G facilitates cell-cell contact by binding E-cadherin in a conserved site, distinct from β-catenin, and localizes β-catenin to the cell adhesion site in early embryos and epithelial cell cultures.[81] Ankyrin-G is enriched at the ventricular zone of the embryonic brain, where it regulates the proliferation of neural progenitor cells. Ankyrin-G loss-of-function increases the proliferation of neural progenitor cells and nuclear β-catenin, probably by disruption of the β-catenin/cadherin interaction.[82]

Classical cadherins form a complex with β-catenin and play a role in cell-cell adhesion.[82,83] Loss of function mutations in classical cadherins leads to decreased cell adhesion, increased cell motility, and an increase in β-catenin release and level of canonical WNT signaling.[84] One study demonstrated a rare microdeletion of classical cadherin CDH8 in a group of individuals suffering from autism and learning disabilities.[85] Classical cadherin CDH9, CDH10, CDH13, and CDH15 mutations have also been encountered in some autism patients. The predicted functional consequence of haploinsufficiencies of these cadherins would be enhanced β-catenin release and activation of the WNT pathway.[86,87]

Dysfunction of the UBE3A gene has been linked to autism, Angelman syndrome, and cancer. UBE3AT485A, a de novo autism-dependent UBE3A mutant that disrupts phosphorylated control of UBE3A activity, converts multiple proteasome subunits to ubiquitin, reduces proteasome subunit abundance and activity, stabilizes nuclear β-catenin, and stimulates canonical WNT type UBE3A signal more effectively than wild type UBE3A.[88]

Rare missense variants have been identified in ASD patients. These variants inhibit DIXDC1 isoform 1 phosphorylation, causing impairment to dendrite and spine growth. These data reveal that DIXDC1 is a regulator of cortical dendrite and synaptic development and provide mechanistic insight into morphological defects associated with neurodevelopmental disorders. DIXDC1 is a positive modulator for WNT signaling and regulates excitatory neuron dendrite development and synapse function in the mouse cortex. MARK1, which is also linked to ASD, phosphorylates DIXDC1 to regulate dendrite and spine development through modulation of the cytoskeletal network in an isoform-specific manner. Mice deficient in DIXDC1 exhibit behavioral disturbances including reduced social interaction that can be mitigated by pharmacological inhibition of GSK3 to up-regulate WNT/β-catenin signaling.[89]

Prostaglandin E2 (PGE2), an endogenous lipid molecule, is linked to ASD. The association between prostaglandin and autism derives from the Möbius sequence with autism and history of misoprostol use during pregnancy.[90] The prostaglandin analogue misoprostol is used for termination of pregnancy as well as for the prevention of stomach ulcers. Four out of seven children (57.1%) with ASD were exposed to misoprostol prenatally.[90,91] Studies have shown that PGE2 interacts with canonical WNT signaling in neuroectodermal (NE-4C) stem cells and that it increased the average speed of migration in WNT-activated neuroectodermal stem NE-4C cells. PGE2 alters distinct cellular phenotypes that are characteristic of WNT-induced NE-4C cells, corresponding to the modified splitting behavior of the cells. Furthermore, expression levels of WNT-target genes (CTNNB1, PTGS2, CCND1, MMP9) were found to increase significantly in response to PGE2 treatment.[92]

Mutations in the neuroligins NLGN3 and NLGN4 have been reported in patients with autism.[93] Such type I transmembrane proteins are neural cell adhesion molecules and are required for synapse formation and development.[94] Studies have demonstrated that WNT/β-catenin signaling directly regulates NLGN3 expression.[95]

SHANK3 is a synaptic scaffold protein enriched in the postsynaptic region of excitatory synapses and plays important roles in the formation, maturation and maintenance of synapses.[96] Findings from genetic studies in patients with ASD suggest a strong relationship between SHANK3 and ASD.[97] Various mutations in the SHANK3 gene have implications for dendritic branching morphology and synaptic transmission.[98]

Haploinsufficiency of the SHANK3 gene causes 22q13.3 deletion syndrome (Phelan-McDermid syndrome), a developmental disorder characterized by speech delay, hypotonia, developmental delay and autistic behavior.[99]

Studies have shown that Shank proteins, in addition to scaffold functions, also play a role in signaling pathways, therefore, thus, Shank3 has been proposed to regulate the WNT signaling pathway by sequestering β-catenin at post-synaptic sites. As a result, heterozygous loss of Shank3, as observed in autistic patients, allows for increased translocation of β-catenin to the nucleus where it may induce transcription of β-catenin-responsive genes.[100]

Taken in its entirety, the available genetic information indicates that not only canonical WNT pathway activation, but also inhibition seems to increase autism risk.


The MECP2 protein plays an important role in certain neurodevelopmental disorders, one of which is Rett syndrome (RTT).[101] Rett syndrome is a rare neurological and developmental disorder that shares some common features with ASD.[102] Patients with RTT generally exhibit normal development during infancy, followed by a period of regression. Abnormal behaviors often include motor function deficits, cognitive impairments, and other symptoms associated with mental retardation.[102,103]

Mutations in genes producing the MECP2 protein are observed in almost all cases of RTT.[104] MECP2 regulates the activity of other genes and plays a role in the growth and communication of nerve cells.[105]

One study showed that restoration of Wnt6, a signaling molecule involved in brain function, eased motor and social behavioral deficits in a mouse model of Rett syndrome. Mice carrying MEPC2 T158A mutation showed a nearly 12-fold reduction in the levels of Wnt6, which plays a critical role in development and adult brain functions. These findings suggested that deficient WNT6 signaling may play a role in RTT development, and restoring its activity may alleviate disease symptoms in the mouse model. To test this hypothesis, it was evaluated whether restoring the WNT6 signal could rescue behavioral difficulties in mice with the RTT-associated MECP2 mutation. To this end, an increase in WNT6 levels was achieved, particularly in the amygdala, a region of the brain involving emotions and behavior. The results indicated that the restoration of the WNT6 signal partially, but significantly, rescued not only social behavioral deficiencies, but also motor difficulties compared to untreated mice. The authors noted that while the amygdala itself is not mainly involved in motor control, it is connected with brain regions that play such a role, and as a result, Wnt6 signaling in the amygdala may indirectly influence motor function. Further analysis revealed that the benefits associated with WNT6 were linked to the restoration of MeCP2 SUMOylation (small ubiquitin-like modifier [SUMO]) and normalized or increased BDNF and IGF-1 protein levels in the amygdala. BDNF and IGF-1 play a role in brain development and nerve cell function. Previous studies have shown that BDNF is impaired in both mouse models and patients with Rett syndrome. BDNF and IGF-1 play a role in brain development and nerve cell function. Prior research showed that BDNF is impaired both in mouse models and people with Rett syndrome. Furthermore, a different study found that that IGF-1 treatment eased disease symptoms in a person with Rett syndrome. Taken in its entirety, these findings suggested that WNT6 may promote MeCP2 SUMOylation through an increase in BDNF and IGF-1 levels.[106]


Although increased spine densities are seen in autism spectrum disorder, spine pruning and maturation defects are seen as well.[107,108] Neural activity is a driving force in development, and sensory experience influences dendritic branching density and maturation of dentritic branching. Experience-dependent spine pruning and maturation has been observed in the mouse primary somatosensory cortex. Using live imaging, it was demonstrated that locally elevating neural activity or cadherin/catenindependent cell adhesion led to enlargement of the stimulated spine and concurrent pruning of its neighbor, an effect dependent on inter-spine distance and N-cadherin motility. Furthermore, selective enrichment of β-catenin in a small proportion of spines in vivo through pre-synaptic manipulations promoted the survival and maturation of β-catenin-enriched spines, at the expense of neighboring spines with lower β-catenin levels. In addition, it was shown that acceleration of spine pruning induced by environmental enrichment was abolished in the absence of endogenous β-catenin. Together, these results demonstrate a critical role of the cadherin/catenin complex in mediating coordinated spine pruning and maturation during neural circuit refinement.[109]

Some of the aforementioned mutations that result in increased WNT signaling lead to increased nuclear translocation of β-catenin. In this case, β-catenin may be unable to adequately form a complex with N-cadherin.[110] Therefore, errors may occur during the critical role of this complex in mediating coordinated spine pruning and maturation.


Some of the mutations associated with WNT signaling and common risk genes demonstrated in different studies and mentioned throughout this study point to an increased risk of cancer in individuals with autism. However, there are studies that report low cancer rates in individuals with autism. As previously mentioned, abnormal activation of the canonical WNT signal plays a role in several forms of cancer. These inconsistent results regarding cancer rates can be attributed to the contribution of mutations that abnormally increase or decrease the WNT/β-catenin signaling in autism spectrum disorders. Further studies to be conducted in the future will shed light upon this subject.

Conflict of Interest

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Financial Disclosure

The authors received no financial support for the research and/or authorship of this article.


  1. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 2004;20:781-810.
  2. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell 2006;127:469-80.
  3. Ozawa M, Baribault H, Kemler R. The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species. EMBO J 1989;8:1711-7.
  4. McCrea PD, Turck CW, Gumbiner B. A homolog of the armadillo protein in Drosophila (plakoglobin) associated with E-cadherin. Science 1991;254:1359-61.
  5. Peifer M, McCrea PD, Green KJ, Wieschaus E, Gumbiner BM. The vertebrate adhesive junction proteins beta-catenin and plakoglobin and the Drosophila segment polarity gene armadillo form a multigene family with similar properties. J Cell Biol 1992;118:681-91.
  6. Xu W, Kimelman D. Mechanistic insights from structural studies of beta-catenin and its binding partners. J Cell Sci 2007;120:3337-44.
  7. Xing Y, Takemaru K, Liu J, Berndt JD, Zheng JJ, Moon RT, et al. Crystal structure of a full-length betacatenin. Structure 2008;16:478-87.
  8. Hagen T, Vidal-Puig A. Characterisation of the phosphorylation of beta-catenin at the GSK-3 priming site Ser45. Biochem Biophys Res Commun 2002;294:324-8.
  9. van Noort M, van de Wetering M, Clevers H. Identification of two novel regulated serines in the N terminus of beta-catenin. Exp Cell Res 2002;276:264-72.
  10. Brembeck FH, Rosário M, Birchmeier W. Balancing cell adhesion and Wnt signaling, the key role of betacatenin. Curr Opin Genet Dev 2006;16:51-9.
  11. Gamallo C, Palacios J, Moreno G, Calvo de Mora J, Suárez A, Armas A. beta-catenin expression pattern in stage I and II ovarian carcinomas : relationship with beta-catenin gene mutations, clinicopathological features, and clinical outcome. Am J Pathol 1999;155:527-36.
  12. Akisik E, Buşra D, Yamaner S, Dalay N. Analysis of b-catenin alterations in colon tumors: a novel exon 3 mutation. Tumour Biol 2011;32:71-6.
  13. Takahashi H, Liu FC. Genetic patterning of the mammalian telencephalon by morphogenetic molecules and transcription factors. Birth Defects Res C Embryo Today 2006;78:256-66.
  14. Mulligan KA, Cheyette BN. Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry. Mol Neuropsychiatry 2017;2:219-46.
  15. Okerlund ND, Cheyette BN. Synaptic Wnt signaling-a contributor to major psychiatric disorders? J Neurodev Disord 2011;3:162-74.
  16. Kwan V, Unda BK, Singh KK. Wnt signaling networks in autism spectrum disorder and intellectual disability. J Neurodev Disord 2016;8:45.
  17. Huelsken J, Behrens J. The Wnt signalling pathway. J Cell Sci 2002;115:3977-8.
  18. Nusse R, Varmus HE. Wnt genes. Cell 1992;69:1073-87.
  19. Veeman MT, Axelrod JD, Moon RT. A second canon. Functions and mechanisms of beta-cateninindependent Wnt signaling. Dev Cell 2003;5:367-77.
  20. Kimelman D, Xu W. beta-catenin destruction complex: insights and questions from a structural perspective. Oncogene 2006;25:7482-91.
  21. Lai SL, Chien AJ, Moon RT. Wnt/Fz signaling and the cytoskeleton: potential roles in tumorigenesis. Cell Res 2009;19:532-45.
  22. Steinbeisser H. Faculty Opinions recommendation of Cthrc1 selectively activates the planar cell polarity pathway of Wnt signaling by stabilizing the Wntreceptor complex. Dev Cell 2008;15:23-36.
  23. van Amerongen R, Nusse R. Towards an integrated view of Wnt signaling in development. Development 2009;136:3205-14.
  24. Kazanskaya O, Glinka A, del Barco Barrantes I, Stannek P, Niehrs C, Wu W. R-Spondin2 is a secreted activator of Wnt/beta-catenin signaling and is required for Xenopus myogenesis. Dev Cell 2004;7:525-34.
  25. Glinka A, Dolde C, Kirsch N, Huang YL, Kazanskaya O, Ingelfinger D, et al. LGR4 and LGR5 are R-spondin receptors mediating Wnt/b-catenin and Wnt/PCP signalling. EMBO Rep 2011;12:1055-61.
  26. Hao HX, Xie Y, Zhang Y, Charlat O, Oster E, Avello M, et al. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature 2012;485:195-200.
  27. de Lau W, Barker N, Low TY, Koo BK, Li VS, Teunissen H, et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 2011;476:293-7.
  28. de Lau W, Peng WC, Gros P, Clevers H. The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength. Genes Dev 2014;28:305-16.
  29. Koo BK, Spit M, Jordens I, Low TY, Stange DE, van de Wetering M, et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature 2012;488:665-9.
  30. Jiang X, Charlat O, Zamponi R, Yang Y, Cong F. Dishevelled promotes Wnt receptor degradation through recruitment of ZNRF3/RNF43 E3 ubiquitin ligases. Mol Cell 2015;58:522-33.
  31. Barker N, Clevers H. Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov 2006;5:997-1014.
  32. Vermeulen L, De Sousa E Melo F, van der Heijden M, Cameron K, de Jong JH, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol 2010;12:468-76.
  33. Seshagiri S, Stawiski EW, Durinck S, Modrusan Z, Storm EE, Conboy CB, et al. Recurrent R-spondin fusions in colon cancer. Nature 2012;488:660-4.
  34. Rusan NM, Peifer M. Original CIN: reviewing roles for APC in chromosome instability. J Cell Biol 2008;181:719-26.
  35. Aoki K, Aoki M, Sugai M, Harada N, Miyoshi H, Tsukamoto T, et al. Chromosomal instability by betacatenin/TCF transcription in APC or beta-catenin mutant cells. Oncogene 2007;26:3511-20.
  36. Zeng G, Germinaro M, Micsenyi A, Monga NK, Bell A, Sood A, et al. Aberrant Wnt/beta-catenin signaling in pancreatic adenocarcinoma. Neoplasia 2006;8:279-89.
  37. White BD, Chien AJ, Dawson DW. Dysregulation of Wnt/b-catenin signaling in gastrointestinal cancers. Gastroenterology 2012;142:219-32.
  38. Jiang X, Hao HX, Growney JD, Woolfenden S, Bottiglio C, Ng N, et al. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc Natl Acad Sci U S A 2013;110:12649-54.
  39. Kadowaki T, Wilder E, Klingensmith J, Zachary K, Perrimon N. The segment polarity gene porcupine encodes a putative multitransmembrane protein involved in Wingless processing. Genes Dev 1996;10:3116-28.
  40. Zhang Y, Morris JP 4th, Yan W, Schofield HK, Gurney A, Simeone DM, et al. Canonical wnt signaling is required for pancreatic carcinogenesis. Cancer Res 2013;73:4909-22.
  41. Morris JP 4th, Cano DA, Sekine S, Wang SC, Hebrok M. Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J Clin Invest 2010;120:508-20.
  42. van de Wetering M, Francies HE, Francis JM, Bounova G, Iorio F, Pronk A, et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 2015;161:933-45.
  43. Boulter L, Guest RV, Kendall TJ, Wilson DH, Wojtacha D, Robson AJ et al. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. J Clin Invest 2015;125:1269-85.
  44. Chan-On W, Nairismägi ML, Ong CK, Lim WK, Dima S, Pairojkul C, et al. Exome sequencing identifies distinct mutational patterns in liver flukerelated and non-infection-related bile duct cancers. Nat Genet 2013;45:1474-8.
  45. Goeppert B, Konermann C, Schmidt CR, Bogatyrova O, Geiselhart L, Ernst C, et al. Global alterations of DNA methylation in cholangiocarcinoma target the Wnt signaling pathway. Hepatology 2014;59:544-54.
  46. Luis TC, Ichii M, Brugman MH, Kincade P, Staal FJ. Wnt signaling strength regulates normal hematopoiesis and its deregulation is involved in leukemia development. Leukemia 2012;26:414- 21.
  47. Lento W, Congdon K, Voermans C, Kritzik M, Reya T. Wnt signaling in normal and malignant hematopoiesis. Cold Spring Harb Perspect Biol 2013;5:a008011.
  48. Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z, et al. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science 2010;327:1650-3.
  49. Yeung J, Esposito MT, Gandillet A, Zeisig BB, Griessinger E, Bonnet D, et al. b-catenin mediates the establishment and drug resistance of MLL leukemic stem cells. Cancer Cell 2010;18:606-18.
  50. Giambra V, Jenkins CE, Lam SH, Hoofd C, Belmonte M, Wang X, et al. Leukemia stem cells in T-ALL require active Hif1a and Wnt signaling. Blood 2015;125:3917-27.
  51. Lu D, Zhao Y, Tawatao R, Cottam HB, Sen M, Leoni LM, et al. Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 2004;101:3118-23.
  52. Lin SY, Xia W, Wang JC, Kwong KY, Spohn B, Wen Y, et al. Beta-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression. Proc Natl Acad Sci U S A 2000;97:4262-6.
  53. Geyer FC, Lacroix-Triki M, Savage K, Arnedos M, Lambros MB, MacKay A, et al. b-catenin pathway activation in breast cancer is associated with triplenegative phenotype but not with CTNNB1 mutation. Mod Pathol 2011;24:209-31.
  54. Li S, Li S, Sun Y, Li L. The expression of b-catenin in different subtypes of breast cancer and its clinical significance. Tumour Biol 2014;35:7693-8.
  55. Liu CC, Prior J, Piwnica-Worms D, Bu G. LRP6 overexpression defines a class of breast cancer subtype and is a target for therapy. Proc Natl Acad Sci U S A 2010;107:5136-41.
  56. Howe LR, Brown AM. Wnt signaling and breast cancer. Cancer Biol Ther 2004;3:36-41.
  57. Klarmann GJ, Decker A, Farrar WL. Epigenetic gene silencing in the Wnt pathway in breast cancer. Epigenetics 2008;3:59-63.
  58. Klauzinska M, Baljinnyam B, Raafat A, RodriguezCanales J, Strizzi L, Greer YE, et al. Rspo2/ Int7 regulates invasiveness and tumorigenic properties of mammary epithelial cells. J Cell Physiol 2012;227:1960-71.
  59. Kypta RM, Waxman J. Wnt/b-catenin signalling in prostate cancer. Nat Rev Urol 2012;9:418-28.
  60. Rivera MN, Kim WJ, Wells J, Driscoll DR, Brannigan BW, Han M, et al. An X chromosome gene, WTX, is commonly inactivated in Wilms tumor. Science 2007;315:642-5.
  61. Major MB, Camp ND, Berndt JD, Yi X, Goldenberg SJ, Hubbert C, et al. Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin signaling. Science 2007;316:1043-6.
  62. Kalani MY, Cheshier SH, Cord BJ, Bababeygy SR, Vogel H, Weissman IL, et al. Wnt-mediated selfrenewal of neural stem/progenitor cells. Proc Natl Acad Sci U S A 2008;105:16970-5.
  63. Jung HY, Jun S, Lee M, Kim HC, Wang X, Ji H, et al. PAF and EZH2 induce Wnt/b-catenin signaling hyperactivation. Mol Cell 2013;52:193-205.
  64. Malanchi I, Huelsken J. Cancer stem cells: never Wnt away from the niche. Curr Opin Oncol 2009;21:41-6.
  65. Nguyen DX, Chiang AC, Zhang XH, Kim JY, Kris MG, Ladanyi M, et al. WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell 2009;138:51-62.
  66. Martin PM, Yang X, Robin N, Lam E, Rabinowitz JS, Erdman CA, et al. A rare WNT1 missense variant overrepresented in ASD leads to increased Wnt signal pathway activation. Transl Psychiatry 2013;3:e301.
  67. Chow ML, Pramparo T, Winn ME, Barnes CC, Li HR, Weiss L, et al. Age-dependent brain gene expression and copy number anomalies in autism suggest distinct pathological processes at young versus mature ages. PLoS Genet 2012;8:e1002592.
  68. Lie DC, Colamarino SA, Song HJ, Désiré L, Mira H, Consiglio A, et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature 2005;437:1370-5.
  69. Liu P, Wakamiya M, Shea MJ, Albrecht U, Behringer RR, Bradley A. Requirement for Wnt3 in vertebrate axis formation. Nat Genet 1999;22:361-5.
  70. Hiester BG, Galati DF, Salinas PC, Jones KR. Neurotrophin and Wnt signaling cooperatively regulate dendritic spine formation. Mol Cell Neurosci 2013;56:115-27.
  71. Wassink TH, Piven J, Vieland VJ, Huang J, Swiderski RE, Pietila J, et al. Evidence supporting WNT2 as an autism susceptibility gene. Am J Med Genet 2001;105:406-13.
  72. Lin PI, Chien YL, Wu YY, Chen CH, Gau SS, Huang YS, et al. The WNT2 gene polymorphism associated with speech delay inherent to autism. Res Dev Disabil 2012;33:1533-40.
  73. Zhou XL, Giacobini M, Anderlid BM, Anckarsäter H, Omrani D, Gillberg C, et al. Association of adenomatous polyposis coli (APC) gene polymorphisms with autism spectrum disorder (ASD). Am J Med Genet B Neuropsychiatr Genet 2007;144B:351-4.
  74. Mohn JL, Alexander J, Pirone A, Palka CD, Lee SY, Mebane L, et al. Adenomatous polyposis coli protein deletion leads to cognitive and autism-like disabilities. Mol Psychiatry 2014;19:1133-42.
  75. Kuechler A, Willemsen MH, Albrecht B, Bacino CA, Bartholomew DW, van Bokhoven H, et al. De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum. Hum Genet 2015;134:97-109.
  76. Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 2006;38:320-3.
  77. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 2014;515:209-15.
  78. Iossifov I, O’Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 2014;515:216-21.
  79. Bi C, Wu J, Jiang T, Liu Q, Cai W, Yu P, et al. Mutations of ANK3 identified by exome sequencing are associated with autism susceptibility. Hum Mutat 2012;33:1635-8.
  80. Hedstrom KL, Ogawa Y, Rasband MN. AnkyrinG is required for maintenance of the axon initial segment and neuronal polarity. J Cell Biol 2008;183:635-40.
  81. Kizhatil K, Davis JQ, Davis L, Hoffman J, Hogan BL, Bennett V. Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos. J Biol Chem 2007;282:26552-61.
  82. Durak O, de Anda FC, Singh KK, Leussis MP, Petryshen TL, Sklar P, et al. Ankyrin-G regulates neurogenesis and Wnt signaling by altering the subcellular localization of b-catenin. Mol Psychiatry 2015;20:388-97.
  83. Arikkath J, Reichardt LF. Cadherins and catenins at synapses: roles in synaptogenesis and synaptic plasticity. Trends Neurosci 2008;31:487-94.
  84. Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science 2004;303:1483-7.
  85. Pagnamenta AT, Khan H, Walker S, Gerrelli D, Wing K, Bonaglia MC, et al. Rare familial 16q21 microdeletions under a linkage peak implicate cadherin 8 (CDH8) in susceptibility to autism and learning disability. J Med Genet 2011;48:48-54.
  86. Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS, et al. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 2009;459:528-33.
  87. Willemsen MH, Fernandez BA, Bacino CA, Gerkes E, de Brouwer AP, Pfundt R, et al. Identification of ANKRD11 and ZNF778 as candidate genes for autism and variable cognitive impairment in the novel 16q24.3 microdeletion syndrome. Eur J Hum Genet 2010;18:429-35.
  88. Yi JJ, Paranjape SR, Walker MP, Choudhury R, Wolter JM, Fragola G, et al. The autism-linked UBE3A T485A mutant E3 ubiquitin ligase activates the Wnt/ b-catenin pathway by inhibiting the proteasome. J Biol Chem 2017;292:12503-15.
  89. Kwan V, Meka DP, White SH, Hung CL, Holzapfel NT, Walker S, et al. DIXDC1 Phosphorylation and Control of Dendritic Morphology Are Impaired by Rare Genetic Variants. Cell Rep 2016;17:1892-904.
  90. Bandim JM, Ventura LO, Miller MT, Almeida HC, Costa AE. Autism and Möbius sequence: an exploratory study of children in northeastern Brazil. Arq Neuropsiquiatr 2003;61:181-5.
  91. Landrigan PJ. What causes autism? Exploring the environmental contribution. Curr Opin Pediatr 2010;22:219-25.
  92. Wong CT, Ahmad E, Li H, Crawford DA. Prostaglandin E2 alters Wnt-dependent migration and proliferation in neuroectodermal stem cells: implications for autism spectrum disorders. Cell Commun Signal 2014;12:19.
  93. Jamain S, Quach H, Betancur C, Råstam M, Colineaux C, Gillberg IC, et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 2003;34:27-9.
  94. Zhang X, Rui M, Gan G, Huang C, Yi J, Lv H, et al. Neuroligin 4 regulates synaptic growth via the bone morphogenetic protein (BMP) signaling pathway at the Drosophila neuromuscular junction. J Biol Chem 2017;292:17991-18005.
  95. Medina MA, Andrade VM, Caracci MO, Avila ME, Verdugo DA, Vargas MF, et al. Wnt/b-catenin signaling stimulates the expression and synaptic clustering of the autism-associated Neuroligin 3 gene. Transl Psychiatry 2018;8:45.
  96. Naisbitt S, Kim E, Tu JC, Xiao B, Sala C, Valtschanoff J, et al. Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/ PSD-95/GKAP complex and cortactin. Neuron 1999;23:569-82.
  97. Uchino S, Waga C. SHANK3 as an autism spectrum disorder-associated gene. Brain Dev 2013;35:106-10.
  98. Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 2007;39:25-7.
  99. Phelan MC, Rogers RC, Saul RA, Stapleton GA, Sweet K, McDermid H, et al. 22q13 deletion syndrome. Am J Med Genet 2001;101:91-9.
  100. Wang X, Xu Q, Bey AL, Lee Y, Jiang YH. Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing autism and Shank3 mutant mice. Mol Autism 2014;5:30.
  101. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methylCpG-binding protein 2. Nat Genet 1999;23:185-8.
  102. Percy AK. Rett syndrome: exploring the autism link. Arch Neurol 2011;68:985-9.
  103. Swanberg SE, Nagarajan RP, Peddada S, Yasui DH, LaSalle JM. Reciprocal co-regulation of EGR2 and MECP2 is disrupted in Rett syndrome and autism. Hum Mol Genet 2009;18:525-34.
  104. Moretti P, Zoghbi HY. MeCP2 dysfunction in Rett syndrome and related disorders. Curr Opin Genet Dev 2006;16:276-81.
  105. Adkins NL, Georgel PT. MeCP2: structure and function. Biochem Cell Biol 2011;89:1-11.
  106. Hsu WL, Ma YL, Liu YC, Tai DJC, Lee EHY. Restoring Wnt6 signaling ameliorates behavioral deficits in MeCP2 T158A mouse model of Rett syndrome. Sci Rep 2020;10:1074.
  107. Hutsler JJ, Zhang H. Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders. Brain Res 2010;1309:83-94.
  108. Barón-Mendoza I, Del Moral-Sánchez I, Martínez-Marcial M, García O, Garzón-Cortés D, GonzálezArenas A. Dendritic complexity in prefrontal cortex and hippocampus of the autistic-like mice C58/J. Neurosci Lett 2019;703:149-55.
  109. Bian WJ, Miao WY, He SJ, Qiu Z, Yu X. Coordinated Spine Pruning and Maturation Mediated by InterSpine Competition for Cadherin/Catenin Complexes. Cell 2015;162:808-22.
  110. Harris TJ, Peifer M. Decisions, decisions: betacatenin chooses between adhesion and transcription. Trends Cell Biol 2005;15:234-7.