Alternative titles; symbols
HGNC Approved Gene Symbol: WNT2
Cytogenetic location: 7q31.2 Genomic coordinates (GRCh38): 7:117,275,451-117,323,058 (from NCBI)
Wainwright et al. (1988) cloned from a human lung cDNA library an expressed gene sequence that was identified by isolation of a methylation-free CpG island from human chromosome 7. (See HISTORY.) The deduced 360-amino acid protein, designated IRP, showed marked similarity to the murine protooncogene Int1 and its Drosophila homolog 'wingless,' but was distinct from the human INT1 gene (WNT1; 164820), which maps to chromosome 12. Like INT1, IRP appears to be a secreted protein; it is cysteine rich with a signal peptide sequence and has 2 potential asn-linked glycosylation sites. Wainwright et al. (1988) suggested that IRP is an additional member of the INT1 growth factor gene family. Northern blot analysis showed IRP expression in placenta and in fetal and adult lung.
Chan et al. (1989) isolated overlapping genomic clones that correspond to the mouse homolog of the IRP gene.
Nusse et al. (1991) suggested that IRP be referred to as WNT2.
Wainwright et al. (1988) identified the IRP gene on chromosome 7q31.
Chan et al. (1989) demonstrated in mouse-hamster somatic cell hybrids that the mouse Irp gene is located on chromosome 6. In addition, they showed that the mouse Irp and Met genes coamplified in lines of spontaneously transformed mouse NIH 3T3 cells, indicating that these genes are closely linked.
Using ribonuclease protection analysis, Huguet et al. (1994) investigated expression of WNT genes, including WNT2, in human cell lines, as well as in normal, benign, and malignant breast tissue. They detected WNT2 in human breast tissue and hypothesized that WNT2 may be associated with abnormal proliferation in breast tissue.
Yu et al. (2012) adapted a microfluidic device for efficient capture of circulating tumor cells from an endogenous mouse pancreatic cancer model and subjected these cells to single-molecule RNA sequencing, identifying Wnt2 as a candidate gene enriched in circulating tumor cells. Expression of WNT2 in pancreatic cancer cells suppressed anoikis, enhanced anchorage-independent sphere formation, and increased metastatic propensity in vivo. This effect is correlated with fibronectin (135600) upregulation and suppressed by inhibition of MAP3K7 (602614). In humans, formation of nonadherent tumor spheres by pancreatic cancer cells was associated with upregulation of multiple WNT genes, and pancreatic circulating tumor cells revealed enrichment for WNT signaling in 5 of 11 cases.
Peng et al. (2013) identified a population of multipotent cardiopulmonary mesoderm progenitors (CPPs) within the posterior pole of the heart that are marked by the expression of Wnt2, Gli1 (165220), and Isl1 (600366). Peng et al. (2013) showed that CPPs arise from cardiac progenitors before lung development. Lineage tracing and clonal analysis demonstrates that CPPs generate the mesoderm lineages within the cardiac inflow tract and lung, including cardiomyocytes, pulmonary vascular and airway smooth muscle, proximal vascular endothelium, and pericyte-like cells. CPPs are regulated by hedgehog (see 600725) expression from the foregut endoderm, which is required for connection of the pulmonary vasculature to the heart. Peng et al. (2013) concluded that taken together, their studies identified a novel population of multipotent cardiopulmonary progenitors that coordinates heart and lung codevelopment that is required for adaptation to terrestrial existence.
Wassink et al. (2001) examined WNT2 as a candidate gene for autism (611015) for the following reasons: first, the WNT family of genes influences the development of numerous organs and systems, including the central nervous system; second, WNT2 is located in the 7q31-q33 region linked to autism and is adjacent to a chromosomal breakpoint in an individual with autism; third, a mouse knockout of the dishevelled-1 (DVL1; 601365) gene, a member of a gene family essential for the function of the WNT pathway, exhibits a behavioral phenotype characterized primarily by diminished social interaction. Wassink et al. (2001) found 2 families containing nonconservative coding sequence variants that segregated with autism. They also identified linkage disequilibrium between a WNT2 3-prime-untranslated region single-nucleotide polymorphism (SNP) and their sample of autism-affected sib pair families and trios (2 parents and 1 affected child). Linkage disequilibrium occurred almost exclusively in a subgroup of affected sib pair families defined by the presence of severe language abnormalities and was also found to be associated with evidence for linkage to 7q. Expression analysis demonstrated WNT2 expression in the human thalamus. In a later study, McCoy et al. (2002) found no significant association between autistic disorder and WNT2 genotypes in either an overall dataset or a language-impaired subset of families. No activating mutation in the coding region of WNT2 was found.
Bird et al. (1985) described so-called HTF (HpaII tiny fragments) islands which are relatively rich in G/C and virtually free of methylation at the CpG dinucleotide. Such regions usually occur at discrete units, 1 to 2 kb long, which can be detected by analysis with methylation-sensitive restriction enzymes. HTF islands are particularly associated with the site of initiation of transcription and the first exons of genes. Both tissue-specific and housekeeping genes have been described in association with HTF islands (Bird, 1987). The characteristics of HTF islands make it possible to isolate selectively regions of the genome that are likely to contain structural genes.
Bird, A. P. CpG islands as gene markers in the vertebrate nucleus. Trends Genet. 3: 342-347, 1987.
Bird, A., Taggart, M., Frommer, M., Miller, O. J., Macleod, D. A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA. Cell 40: 91-99, 1985. [PubMed: 2981636] [Full Text: https://doi.org/10.1016/0092-8674(85)90312-5]
Chan, A. M.-L., Hilkens, J., Kroezen, V., Mitchell, P. J., Scambler, P., Wainwright, B. J., Williamson, R., Cooper, C. S. Molecular cloning and localization to chromosome 6 of mouse INT1L1 gene. Somat. Cell Molec. Genet. 15: 555-562, 1989. [PubMed: 2531931] [Full Text: https://doi.org/10.1007/BF01534916]
Huguet, E. L., McMahon, J. A., McMahon, A. P., Bicknell, R., Harris, A. L. Differential expression of human Wnt genes 2, 3, 4, and 7B in human breast cell lines and normal and disease states of human breast tissue. Cancer Res. 54: 2615-2621, 1994. [PubMed: 8168088]
McCoy, P. A., Shao, Y., Wolpert, C. M., Donnelly, S. L., Ashley-Koch, A., Abel, H. L., Ravan, S. A., Abramson, R. K., Wright, H. H., DeLong, G. R., Cuccaro, M. L., Gilbert, J. R., Pericak-Vance, M. A. No association between the WNT2 gene and autistic disorder. Am. J. Med. Genet. 114: 106-109, 2002. [PubMed: 11840514] [Full Text: https://doi.org/10.1002/ajmg.10182]
Nusse, R., Brown, A., Papkoff, J., Scambler, P., Shackleford, G., McMahon, A., Moon, R., Varmus, H. A new nomenclature for int-1 and related genes: the Wnt gene family. Cell 64: 231-232, 1991. [PubMed: 1846319] [Full Text: https://doi.org/10.1016/0092-8674(91)90633-a]
Peng, T., Tian, Y., Boogerd, C. J., Lu, M. M., Kadzik, R. S., Stewart, K. M., Evans, S. M., Morrisey, E. E. Coordination of heart and lung co-development by a multipotent cardiopulmonary progenitor. Nature 500: 589-592, 2013. [PubMed: 23873040] [Full Text: https://doi.org/10.1038/nature12358]
Wainwright, B. J., Scambler, P. J., Stanier, P., Watson, E. K., Bell, G., Wicking, C., Estivill, X., Courtney, M., Bour, A., Pedersen, P. S., Williamson, R., Farrall, M. Isolation of a human gene with protein sequence similarity to human and murine int-1 and the Drosophila segment polarity mutant wingless. EMBO J. 7: 1743-1748, 1988. [PubMed: 2971536] [Full Text: https://doi.org/10.1002/j.1460-2075.1988.tb03003.x]
Wassink, T. H., Piven, J., Vieland, V. J., Huang, J., Swiderski, R. E., Pietila, J., Braun, T., Beck, G., Folstein, S. E., Haines, J. L., Sheffield, V. C. Evidence supporting WNT2 as an autism susceptibility gene. Am. J. Med. Genet. 105: 406-413, 2001. [PubMed: 11449391] [Full Text: https://doi.org/10.1002/ajmg.1401]
Yu, M., Ting, D. T., Stott, S. L., Wittner, B. S., Ozsolak, F., Paul, S., Ciciliano, J. C., Smas, M. E., Winokur, D., Gilman, A. J., Ulman, M. J., Xega, K., and 11 others. RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis. Nature 487: 510-513, 2012. Note: Erratum: Nature 490: 570 only, 2012. [PubMed: 22763454] [Full Text: https://doi.org/10.1038/nature11217]