Alternative titles; symbols
HGNC Approved Gene Symbol: WNT5A
Cytogenetic location: 3p14.3 Genomic coordinates (GRCh38): 3:55,465,715-55,505,263 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p14.3 | Robinow syndrome, autosomal dominant 1 | 180700 | Autosomal dominant | 3 |
The WNTs comprise a large class of secreted proteins that control essential developmental processes such as embryonic patterning, cell growth, migration, and differentiation. The well-known canonical WNT signaling pathway involves WNT proteins binding to Frizzled (see, e.g., FZD1; 603408) receptors that induce beta-catenin (CTNNB1; 116806) stabilization and entry into the nucleus, where it affects gene transcription. The WNT5A gene encodes a WNT protein involved in both the canonical and noncanonical signaling pathways, depending upon the receptor context (summary by Mikels and Nusse, 2006).
Using degenerate PCR and cDNA library screening to search for mouse genes related to Wnt1, Gavin et al. (1990) identified 6 new members of the Wnt gene family, including Wnt5a. The Wnt genes encode 38- to 43-kD cysteine-rich putative glycoproteins, which have features typical of secreted growth factors: a hydrophobic signal sequence and 21 conserved cysteine residues whose relative spacing is maintained. Northern blot analysis detected expression of Wnt5a in brain, lung, and heart. At least 5 distinct Wnt5a transcripts were observed, which Gavin et al. (1990) hypothesized were due to transcript variability 5-prime to the initiation methionine. In situ hybridization detected a complex spatial and temporal pattern of Wnt5a in the mouse, including expression in the developing central nervous system, limbs, facial processes, and the posterior region of the fetus.
Clark et al. (1993) cloned and sequenced several overlapping cDNAs encoding approximately 4.1 kb of the human homolog of Wnt5A. Expression of the human gene, symbolized WNT5A, was detected only in neonatal heart and lung.
He et al. (1997) showed that human frizzled-5 (601723) is a receptor for the Wnt5A ligand.
Mikels and Nusse (2006) demonstrated that mouse Wnt5a can inhibit canonical Wnt signaling via binding to the Ror2 (602337) receptor. However, Wnt5a also induced beta-catenin accumulation and signaling In the presence of Fzd4 (604579) and LRP5 (603506). The findings indicated that the outcome of WNT5A signaling is dependent upon the type of receptor.
Witze et al. (2008) demonstrated that acute responses to Wnt5a involve recruitment of actin, myosin IIB (160742), frizzled-3 (606143), and melanoma cell adhesion molecule (155735) into an intracellular structure in a melanoma cell line. In the presence of a chemokine gradient, this Wnt-mediated receptor-actin-myosin polarity structure accumulates asymmetrically at the cell periphery, where it triggers membrane contractility and nuclear movement in the direction of membrane retraction. The process requires endosome trafficking, is associated with multivesicular bodies, and is regulated by Wnt5a through the small guanosine triphosphates Rab4 (179511) and RhoB (165370). Thus, Witze et al. (2008) concluded that cell-autonomous mechanisms allow Wnt5a to control cell orientation, polarity, and directional movement in response to positional cues from chemokine gradients.
Zhang et al. (2007) found that downregulation of Dvl (DVL1; 601365) abrogated axon differentiation in cultured embryonic rat hippocampal neurons, whereas overexpression of Dvl resulted in multiple axon formation. A complex of PAR3 (PARD3; 606745), PAR6 (PARD6A; 607484), and an atypical protein kinase C (aPKC), such as PKC-zeta (PRKCZ; 176982), is required for axon-dendrite differentiation, and Zhang et al. (2007) found that Dvl associated with Pkc-zeta in rat brain and transfected human embryonic kidney cells. The interaction of Dvl with Pkc-zeta resulted in stabilization and activation of Pkc-zeta. Expression of dominant-negative Pkc-zeta attenuated multiple axon formation due to Dvl overexpression in neurons, and overexpression of Pkc-zeta prevented axon loss due to Dvl downregulation. Wnt5a activated Pkc-zeta and promoted axon differentiation, and downregulation of Dvl or inhibition of Pkc-zeta attenuated the Wnt5a effect on axon differentiation. Zhang et al. (2007) concluded that WNT5A and DVL promote axon differentiation mediated by the PAR3-PAR6-aPKC complex.
Stefater et al. (2011) showed that during development, retinal myeloid cells produce Wnt ligands to regulate blood vessel branching. In the mouse retina, where angiogenesis occurs postnatally, somatic deletion in retinal myeloid cells of the Wnt ligand transporter Wntless (611574) results in increased angiogenesis in the deeper layers. Stefater et al. (2011) also showed that mutation of Wnt5a and Wnt11 (603699) results in increased angiogenesis and that these ligands elicit retinal myeloid cell responses via a noncanonical Wnt pathway. Using cultured myeloid-like cells and retinal myeloid cell somatic deletion of Flt1 (165070), Stefater et al. (2011) showed that Flt1, a naturally occurring inhibitor of VEGF (192240), is an effector of Wnt-dependent suppression of angiogenesis by retinal myeloid cells. Stefater et al. (2011) concluded that resident myeloid cells can use a noncanonical, Wnt-Flt1 pathway to suppress angiogenic branching.
Miyoshi et al. (2012) found that Wnt5a, a noncanonical Wnt ligand, was required for intestinal crypt regeneration after injury in mice. Unlike controls, Wnt5a-deficient mice maintained an expanded population of proliferative epithelial cells in the wound. Miyoshi et al. (2012) used an in vitro system to enrich for intestinal epithelial stem cells to discover that Wnt5a inhibits proliferation of these cells. Surprisingly, the effects of Wnt5a were mediated by activation of TGF-beta (190180) signaling. Miyoshi et al. (2012) concluded that their findings suggested a Wnt5a-dependent mechanism for forming new crypt units to reestablish homeostasis.
Florian et al. (2013) reported an unexpected shift from canonical to noncanonical Wnt signaling in mice due to elevated expression of Wnt5a in aged hematopoietic stem cells (HSCs), which causes stem cell aging. Wnt5a treatment of young HSCs induced aging-associated stem cell apolarity, reduction of regenerative capacity, and an aging-like myeloid-lymphoid differentiation skewing via activation of the small Rho GTPase Cdc42 (116952). Conversely, Wnt5a haploinsufficiency attenuated HSC aging, whereas stem cell-intrinsic reduction of Wnt5a expression resulted in functionally rejuvenated aged HSCs. Florian et al. (2013) concluded that the data demonstrated a critical role for stem cell-intrinsic noncanonical Wnt5a signaling in HSC aging.
Miyamoto et al. (2015) established single-cell RNA sequencing profiles of 77 intact circulating tumor cells (CTCs) isolated from 13 patients (mean 6 CTCs per patient) with prostate cancer (see 176807), by using microfluidic enrichment. Single CTCs from each individual displayed considerable heterogeneity, including expression of androgen receptor (AR; 313700) gene mutations and splicing variants. Retrospective analysis of CTCs from patients progressing under treatment with an AR inhibitor, compared with untreated cases, indicated activation of noncanonical Wnt signaling (p = 0.0064). Ectopic expression of Wnt5a in prostate cancer cells attenuated the antiproliferative effect of AR inhibition, whereas its suppression in drug-resistant cells restored partial sensitivity, a correlation also evident in an established mouse model. Thus, single-cell analysis of prostate CTCs reveals heterogeneity in signaling pathways that could contribute to treatment failure.
Using a combination of Southern blotting, PCR amplification, and in situ hybridization, Clark et al. (1993) mapped the WNT5A gene to 3p21-p14.
Autosomal dominant Robinow syndrome-1 (DRS1; 180700) is characterized by hypertelorism, craniofacial dysmorphism, short stature, and mesomelic shortening of the limbs. Noting that Wnt5a-null mice exhibit features of Robinow syndrome and that WNT5A interacts with ROR2 (602337), which is mutated in autosomal recessive Robinow syndrome (RRS; 268310), Person et al. (2010) analyzed the WNT5A gene in affected members of the family with autosomal dominant Robinow syndrome originally reported by Robinow et al. (1969) and identified a pathogenic heterozygous mutation (C182R; 164975.0001). A different heterozygous mutation in the WNT5A gene (C83S; 164975.0002) was found in an unrelated patient with sporadic occurrence of the disorder. Mutations in the WNT5A gene were not found in 23 additional unrelated patients with a clinical diagnosis of dominant Robinow syndrome, suggesting genetic heterogeneity. Functional expression assays in zebrafish embryos showed that the mutant proteins represented hypomorphic alleles rather than dominant-negative mutations. The findings implicated the WNT5A/ROR2 pathway in human craniofacial, skeletal, and genital development.
In affected members of 3 families with autosomal dominant Robinow syndrome, Roifman et al. (2015) identified 2 different heterozygous missense mutations in the WNT5A gene (Y86C, 164975.0003 and C69Y, 164975.0004). The mutation in the first family was found by whole-exome sequencing. Functional studies of the variants were not performed, but molecular modeling indicated that all 4 mutations found to date, including those reported by Person et al. (2010), occurred on 1 side of the protein.
Oishi et al. (2003) found that both Wnt5a-null and Ror2 (602337)-null mice showed dwarfism, facial abnormalities, short limbs and tails, dysplasia of lungs and genitals, and ventricular septal defects. In vitro binding assays revealed that Wnt5a binds to the Ror2 and activates the noncanonical Wnt pathway. The findings indicated that Wnt5a and Ror2 interact physically and functionally, and suggested that Ror2 acts as a receptor for Wnt5a to activate noncanonical Wnt signaling.
Wnt5a -/- mice are grossly abnormal and die shortly after birth due to multiple defects (Yamaguchi et al., 1999). Schleiffarth et al. (2007) found 100% penetrance of cardiac outflow tract abnormalities in 19 Wnt5a -/- mice, including persistent truncus arteriosus, double-outlet right ventricle, transposition of the great arteries, large subarterial ventricular septal defect, and several abnormalities of the aortic arch. Wnt5a was expressed in pharyngeal mesoderm in normal mouse embryos at embryonic days 9.5 and 10.5, and in myocardial cell layer of the conotruncus at day 10.5. By day 11.5, Wnt5a was expressed in paratracheal and parapharyngeal mesenchyme. A similar expression pattern was detected in the developing quail. Wnt5a deletion did not affect formation of the secondary or anterior heart field or initiation of migration of cardiac neural crest (CNC) cells. However, it did reduce expression of plexin A2 (PLXNA2; 601054) at a time when CNC cell-derived mesenchyme condenses to form an aortopulmonary septum. Treatment of cultured chicken CNC cells with Wnt5a elicited calcium transients, suggesting that Wnt5a is involved in the calcium, but not planar cell polarity, signaling pathway. Schleiffarth et al. (2007) concluded that WNT5A acts as a local morphogen that signals to CNC cells as they reorganize to form the aortopulmonary septum.
Metacarpals in the synpolydactyly homolog (spdh) mouse, which carries a mutation in the Hoxd13 (142989) homeobox gene, are transformed to carpal-like bones with cuboid shape that lack cortical bone and perichondrium and are surrounded by a joint surface. Kuss et al. (2014) found that metacarpal defects in spdh mice were due, at least in part, to defective Wnt5 signaling. Handplates of spdh embryos showed reduced expression of Wnt5a and Wnt5b, concomitant with defects in cell polarity in metacarpal growth plates and perichondrium. Visible defects in cell polarity were accompanied by increased staining for beta-catenin in the perichondral region of metacarpals. Exogenous Hoxd13 or Wnt5a partly rescued cell polarity defects in perichondrium of spdh mice. In vitro, Hoxd13, but not Hoxd13 with the spdh mutation, induced Wnt5a expression.
The paper by Ford et al. (2009) concerning WNT5A signaling in estrogen receptor-negative breast cancer cells was retracted.
In 7 affected members of a family with autosomal dominant Robinow syndrome-1 (DRS1; 180700) originally reported by Robinow et al. (1969), Person et al. (2010) identified a heterozygous 544/545CT-TC change in exon 4 of the WNT5A gene, resulting in a cys182-to-arg (C182R) substitution at a highly conserved residue. The mutation segregated with the disorder in the family and was not found in 196 controls. Functional expression assays in zebrafish embryos showed that the mutant protein represented a hypomorphic allele rather than a dominant-negative mutation.
In a man with sporadic Robinow syndrome-1 (DRS1; 180700), Person et al. (2010) identified a heterozygous 248G-C transversion in exon 3 of the WNT5A gene, resulting in a cys83-to-ser (C83S) substitution in a highly conserved cysteine residue. The patient had marked hypertelorism, short nose, short stature, and mesomelic limb shortening. The mutation was not found in 173 control DNA samples. Functional expression assays in zebrafish embryos showed that the mutant protein represented a hypomorphic allele rather than a dominant-negative mutation.
In a mother and son of Caucasian origin with autosomal dominant Robinow syndrome-1 (DRS1; 180700), Roifman et al. (2015) identified a heterozygous c.257A-G transition in the WNT5A gene, resulting in a tyr86-to-cys (Y86C) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, occurred as a de novo event in the mother. The same heterozygous Y86C mutation was subsequently found by direct sequencing in a Turkish father and daughter with the disorder. Functional studies of the variant were not performed.
In a boy with autosomal dominant Robinow syndrome-1 (DRS1; 180700), Roifman et al. (2015) identified a de novo heterozygous c.206G-A transition in the WNT5A gene, resulting in a cys69-to-tyr (C69Y) substitution. Functional studies of the variant were not performed.
Clark, C. C., Cohen, I., Eichstetter, I., Cannizzaro, L. A., McPherson, J. D., Wasmuth, J. J., Iozzo, R. V. Molecular cloning of the human proto-oncogene Wnt-5A and mapping of the gene (WNT5A) to chromosome 3p14-p21. Genomics 18: 249-260, 1993. [PubMed: 8288227] [Full Text: https://doi.org/10.1006/geno.1993.1463]
Florian, M. C., Nattamai, K. J., Dorr, K., Marka, G., Uberle, B., Vas, V., Eckl, C., Andra, I., Schiemann, M., Oostendorp, R. A. J., Scharffetter-Kochanek, K., Kestler, H. A., Zheng, Y., Geiger, H. A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing. Nature 503: 392-396, 2013. [PubMed: 24141946] [Full Text: https://doi.org/10.1038/nature12631]
Ford, C. E., Ekstrom, E. J., Andersson, T. Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells. Proc. Nat. Acad. Sci. 106: 3919-3924, 2009. Note: Retraction: Proc. Nat. Acad. Sci. 107: 22360 only, 2010. [PubMed: 19237581] [Full Text: https://doi.org/10.1073/pnas.0809516106]
Gavin, B. J., McMahon, J. A., McMahon, A. P. Expression of multiple novel Wnt-1/int-1-related genes during fetal and adult mouse development. Genes Dev. 4: 2319-2332, 1990. [PubMed: 2279700] [Full Text: https://doi.org/10.1101/gad.4.12b.2319]
He, X., Saint-Jeannet, J.-P., Wang, Y., Nathans, J., Dawid, I., Varmus, H. A member of the frizzled protein family mediating axis induction by Wnt-5A. Science 275: 1652-1654, 1997. [PubMed: 9054360] [Full Text: https://doi.org/10.1126/science.275.5306.1652]
Kuss, P., Kraft, K., Stumm, J., Ibrahim, D., Vallecillo-Garcia, P., Mundlos, S., Stricker, S. Regulation of cell polarity in the cartilage growth plate and perichondrium of metacarpal elements by HOXD13 and WNT5A. Dev. Biol. 385: 83-93, 2014. [PubMed: 24161848] [Full Text: https://doi.org/10.1016/j.ydbio.2013.10.013]
Mikels, A. J., Nusse, R. Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. PLoS Biol. 4: e115, 2006. Note: Electronic Article. [PubMed: 16602827] [Full Text: https://doi.org/10.1371/journal.pbio.0040115]
Miyamoto, D. T., Zheng, Y., Wittner, B. S., Lee, R. J., Zhu, H., Broderick, K. T., Desai, R., Fox, D. B., Brannigan, B. W., Trautwein, J., Arora, K. S., Desai, N., and 11 others. RNA-seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science 349: 1351-1365, 2015. [PubMed: 26383955] [Full Text: https://doi.org/10.1126/science.aab0917]
Miyoshi, H., Ajima, R., Luo, C. T., Yamaguchi, T. P., Stappenbeck, T. S. Wnt5a potentiates TGF-beta signaling to promote colonic crypt regeneration after tissue injury. Science 338: 108-113, 2012. [PubMed: 22956684] [Full Text: https://doi.org/10.1126/science.1223821]
Oishi, I., Suzuki, H., Onishi, N., Takada, R., Kani, S., Ohkawara, B., Koshida, I., Suzuki, K., Yamada, G., Schwabe, G. C., Mundlos, S., Shibuya, H., Takada, S., Minami, Y. The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes Cells 8: 645-654, 2003. [PubMed: 12839624] [Full Text: https://doi.org/10.1046/j.1365-2443.2003.00662.x]
Person, A. D., Beiraghi, S., Sieben, C. M., Hermanson, S., Neumann, A. N., Robu, M. E., Schleiffarth, J. R., Billington, C. J., Jr., van Bokhoven, H., Hoogeboom, J. M., Mazzeu, J. F., Petryk, A., Schimmenti, L. A., Brunner, H. G., Ekker, S. C., Lohr, J. L. WNT5A mutations in patients with autosomal dominant Robinow syndrome. Dev. Dyn. 239: 327-337, 2010. [PubMed: 19918918] [Full Text: https://doi.org/10.1002/dvdy.22156]
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Roifman, M., Marcelis, C. L. M., Paton, T., Marshall, C., Silver, R., Lohr, J. L., Yntema, H. G., Venselaar, H., Kayserili, H., van Bon, B., Seaward, G., FORGE Canada Consortium, Brunner, H. G., Chitayat, D. De novo WNT5A-associated autosomal dominant Robinow syndrome suggests specificity of genotype and phenotype. Clin. Genet. 87: 34-41, 2015. [PubMed: 24716670] [Full Text: https://doi.org/10.1111/cge.12401]
Schleiffarth, J. R., Person, A. D., Martinsen, B. J., Sukovich, D. J., Neumann, A., Baker, C. V. H., Lohr, J. L., Cornfield, D. N., Ekker, S. C., Petryk, A. Wnt5a is required for cardiac outflow tract septation in mice. Pediat. Res. 61: 386-391, 2007. [PubMed: 17515859] [Full Text: https://doi.org/10.1203/pdr.0b013e3180323810]
Stefater, J. A., III, Lewkowich, I., Rao, S., Mariggi, G., Carpenter, A. C., Burr, A. R., Fan, J., Ajima, R., Molkentin, J. D., Williams, B. O., Wills-Karp, M., Pollard, J. W., Yamaguchi, T., Ferrara, N., Gerhardt, H., Lang, R. A. Regulation of angiogenesis by a non-canonical Wnt-Flt1 pathway in myeloid cells. Nature 474: 511-515, 2011. [PubMed: 21623369] [Full Text: https://doi.org/10.1038/nature10085]
Witze, E. S., Litman, E. S., Argast, G. M., Moon, R. T., Ahn, N. G. Wnt5a control of cell polarity and directional movement by polarized redistribution of adhesion receptors. Science 320: 365-369, 2008. [PubMed: 18420933] [Full Text: https://doi.org/10.1126/science.1151250]
Yamaguchi, T. P., Bradley, A., McMahon, A. P., Jones, S. A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. Development 126: 1211-1223, 1999. [PubMed: 10021340] [Full Text: https://doi.org/10.1242/dev.126.6.1211]
Zhang, X., Zhu, J., Yang, G.-Y., Wang, Q.-J., Qian, L., Chen, Y.-M., Chen, F., Tao, Y., Hu, H.-S., Wang, T., Luo, Z.-G. Dishevelled promotes axon differentiation by regulating atypical protein kinase C. Nature Cell Biol. 9: 743-754, 2007. [PubMed: 17558396] [Full Text: https://doi.org/10.1038/ncb1603]