WNT3A explained

Protein Wnt-3a is a protein that in humans is encoded by the WNT3A gene.^[1]

The WNT gene family consists of structurally related genes that encode secreted signaling proteins. These proteins have are critical in tissue homeostasis, embryonic development, and disease.

Signaling and Related Genes

WNT3A is highly related to the WNT3 gene in sequence and protein function. WNT3A and WNT3 signal similarly through primarily the beta-catenin/Tcf pathway. WNT3A is located in the genome beside the WNT9A gene across many vertebrates. Similarly, the WNT3 gene occurs in the genome beside the WNT9B gene. WNT9A and WNT9B signal through the beta-catenin/Tcf pathway but do not play related roles as WNT3A and WNT3 in the same cellular processes.

Role in Disease

WNT3A is not linked to particular genetic disorder in humans. Mice that have a genetic mutation in the WNT3A die during early embryogenesis and fail to correctly form axial tissues.^[2] Rodent Wnt3a promotes the beta-catenin/Tcf pathway which is tumor inducing and can cause cancer when expressed in particular cell populations.^[3]

Role in embryonic development

Embryonic development is the process where the body plan is created. From studies in vertebrate model systems we can infer the roles of particular genes in human anatomical structures. Wnt3a plays a role in these processes:

Wnt3A patterns a multipotent stem cell population that form neurons, muscles, bones, and cartilage of the torso region. Wnt3a instructs these multipotent stems cells to form muscle, bone, and cartilage progenitors over forming neurons.^[4] Wnt3A also regulates the Notch pathway to control the segmentation clock needed for normal torso development ^{[5] [6]}

Left-Right patterning

Wnt3a is in a signaling pathway that activates the gene Nodal which is left side signaling determinant ^[7]

Intestine - Colon

The colon portion of the gastrointestinal tract is completely dependent on Wnt3a and Wnt3a selectively causes the growth of colon progenitors ^[8]

Neural crest

Wnt3a expands neural crest cells during early development ^[9]

Blood cells

Wnt3a promotes hematopoietic stem cell self-renewal. Wnt3a is needed for myeloid but not B-lymphoid development at the progenitor level, and affected immature thymocyte differentiation ^[10]

Brain - Hippocampus

Wnt3a is needed for formation of the hippocampus portion of the brain ^[11]

Teeth

Wnt3a promotes stem cell properties of dental pulp stem cells ^[12]

Further reading

• Smolich BD, McMahon JA, McMahon AP, Papkoff J . Wnt family proteins are secreted and associated with the cell surface . Molecular Biology of the Cell . 4 . 12 . 1267–75 . December 1993 . 8167409 . 275763 . 10.1091/mbc.4.12.1267 .
• Huguet EL, McMahon JA, McMahon AP, Bicknell R, Harris AL . 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 Research . 54 . 10 . 2615–21 . May 1994 . 8168088 .
• Gazit A, Yaniv A, Bafico A, Pramila T, Igarashi M, Kitajewski J, Aaronson SA . Human frizzled 1 interacts with transforming Wnts to transduce a TCF dependent transcriptional response . Oncogene . 18 . 44 . 5959–66 . October 1999 . 10557084 . 10.1038/sj.onc.1202985 . free .
• Tanaka K, Okabayashi K, Asashima M, Perrimon N, Kadowaki T . The evolutionarily conserved porcupine gene family is involved in the processing of the Wnt family . European Journal of Biochemistry . 267 . 13 . 4300–11 . July 2000 . 10866835 . 10.1046/j.1432-1033.2000.01478.x .
• Katoh M . Regulation of WNT3 and WNT3A mRNAs in human cancer cell lines NT2, MCF-7, and MKN45 . International Journal of Oncology . 20 . 2 . 373–7 . February 2002 . 11788904 . 10.3892/ijo.20.2.373 .
• Katoh M . Molecular cloning and expression of mouse Wnt14, and structural comparison between mouse Wnt14-Wnt3a gene cluster and human WNT14-WNT3A gene cluster . International Journal of Molecular Medicine . 9 . 3 . 221–7 . March 2002 . 11836627 . 10.3892/ijmm.9.3.221 .
• Filali M, Cheng N, Abbott D, Leontiev V, Engelhardt JF . Wnt-3A/beta-catenin signaling induces transcription from the LEF-1 promoter . The Journal of Biological Chemistry . 277 . 36 . 33398–410 . September 2002 . 12052822 . 10.1074/jbc.M107977200 . free .
• Hering H, Sheng M . Direct interaction of Frizzled-1, -2, -4, and -7 with PDZ domains of PSD-95 . FEBS Letters . 521 . 1–3 . 185–9 . June 2002 . 12067714 . 10.1016/S0014-5793(02)02831-4 . 39243103 . free .
• Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA . 6 . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proceedings of the National Academy of Sciences of the United States of America . 99 . 26 . 16899–903 . December 2002 . 12477932 . 139241 . 10.1073/pnas.242603899 . 2002PNAS...9916899M . free .
• Hino S, Michiue T, Asashima M, Kikuchi A . Casein kinase I epsilon enhances the binding of Dvl-1 to Frat-1 and is essential for Wnt-3a-induced accumulation of beta-catenin . The Journal of Biological Chemistry . 278 . 16 . 14066–73 . April 2003 . 12556519 . 10.1074/jbc.M213265200 . free .
• Qiang YW, Endo Y, Rubin JS, Rudikoff S . Wnt signaling in B-cell neoplasia . Oncogene . 22 . 10 . 1536–45 . March 2003 . 12629517 . 10.1038/sj.onc.1206239 . free .
• Hocevar BA, Mou F, Rennolds JL, Morris SM, Cooper JA, Howe PH . Regulation of the Wnt signaling pathway by disabled-2 (Dab2) . The EMBO Journal . 22 . 12 . 3084–94 . June 2003 . 12805222 . 162138 . 10.1093/emboj/cdg286 .
• Liu G, Bafico A, Harris VK, Aaronson SA . A novel mechanism for Wnt activation of canonical signaling through the LRP6 receptor . Molecular and Cellular Biology . 23 . 16 . 5825–35 . August 2003 . 12897152 . 166321 . 10.1128/MCB.23.16.5825-5835.2003 . Stuart A. Aaronson .
• Swiatek W, Tsai IC, Klimowski L, Pepler A, Barnette J, Yost HJ, Virshup DM . Regulation of casein kinase I epsilon activity by Wnt signaling . The Journal of Biological Chemistry . 279 . 13 . 13011–7 . March 2004 . 14722104 . 10.1074/jbc.M304682200 . free .
• Zilberberg A, Yaniv A, Gazit A . The low density lipoprotein receptor-1, LRP1, interacts with the human frizzled-1 (HFz1) and down-regulates the canonical Wnt signaling pathway . The Journal of Biological Chemistry . 279 . 17 . 17535–42 . April 2004 . 14739301 . 10.1074/jbc.M311292200 . free .
• Lu W, Yamamoto V, Ortega B, Baltimore D . Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite outgrowth . Cell . 119 . 1 . 97–108 . October 2004 . 15454084 . 10.1016/j.cell.2004.09.019 . 18567677 . free .
• Capurro MI, Shi W, Sandal S, Filmus J . Processing by convertases is not required for glypican-3-induced stimulation of hepatocellular carcinoma growth . The Journal of Biological Chemistry . 280 . 50 . 41201–6 . December 2005 . 16227623 . 10.1074/jbc.M507004200 . free .
• Thrasivoulou C, Millar M, Ahmed A . Activation of intracellular calcium by multiple Wnt ligands and translocation of β-catenin into the nucleus: a convergent model of Wnt/Ca2+ and Wnt/β-catenin pathways . The Journal of Biological Chemistry . 288 . 50 . 35651–9 . December 2013 . 24158438 . 3861617 . 10.1074/jbc.M112.437913 . free .

Notes and References

1. Web site: Entrez Gene: WNT3A wingless-type MMTV integration site family, member 3A.
2. Yoshikawa Y, Fujimori T, McMahon AP, Takada S . Evidence that absence of Wnt-3a signaling promotes neuralization instead of paraxial mesoderm development in the mouse . Developmental Biology . 183 . 2 . 234–42 . March 1997 . 9126297 . 10.1006/dbio.1997.8502 . free .
3. Pashirzad M, Fiuji H, Khazei M, Moradi-Binabaj M, Ryzhikov M, Shabani M, Avan A, Hassanian SM . 6 . Role of Wnt3a in the pathogenesis of cancer, current status and prospective . Molecular Biology Reports . 46 . 5 . 5609–5616 . October 2019 . 31236761 . 10.1007/s11033-019-04895-4 . 195329662 .
4. Garriock RJ, Chalamalasetty RB, Kennedy MW, Canizales LC, Lewandoski M, Yamaguchi TP . Lineage tracing of neuromesodermal progenitors reveals novel Wnt-dependent roles in trunk progenitor cell maintenance and differentiation . Development . 142 . 9 . 1628–38 . May 2015 . 25922526 . 4419273 . 10.1242/dev.111922 .
5. Aulehla A, Wehrle C, Brand-Saberi B, Kemler R, Gossler A, Kanzler B, Herrmann BG . Wnt3a plays a major role in the segmentation clock controlling somitogenesis . Developmental Cell . 4 . 3 . 395–406 . March 2003 . 12636920 . 10.1016/s1534-5807(03)00055-8 . free .
6. Nakaya MA, Biris K, Tsukiyama T, Jaime S, Rawls JA, Yamaguchi TP . Wnt3a links left-right determination with segmentation and anteroposterior axis elongation . Development . 132 . 24 . 5425–36 . December 2005 . 16291790 . 1389788 . 10.1242/dev.02149 .
7. Nakaya MA, Biris K, Tsukiyama T, Jaime S, Rawls JA, Yamaguchi TP . Wnt3a links left-right determination with segmentation and anteroposterior axis elongation . Development . 132 . 24 . 5425–36 . December 2005 . 16291790 . 1389788 . 10.1242/dev.02149 .
8. Garriock RJ, Chalamalasetty RB, Zhu J, Kennedy MW, Kumar A, Mackem S, Yamaguchi TP . A dorsal-ventral gradient of Wnt3a/β-catenin signals controls mouse hindgut extension and colon formation . Development . 147 . 8 . dev185108 . April 2020 . 32156757 . 7174843 . 10.1242/dev.185108 .
9. Ikeya M, Lee SM, Johnson JE, McMahon AP, Takada S . Wnt signalling required for expansion of neural crest and CNS progenitors . Nature . 389 . 6654 . 966–70 . October 1997 . 9353119 . 10.1038/40146 . 1997Natur.389..966I . 4359867 .
10. Luis TC, Weerkamp F, Naber BA, Baert MR, de Haas EF, Nikolic T, Heuvelmans S, De Krijger RR, van Dongen JJ, Staal FJ . 6 . Wnt3a deficiency irreversibly impairs hematopoietic stem cell self-renewal and leads to defects in progenitor cell differentiation . Blood . 113 . 3 . 546–54 . January 2009 . 18832654 . 10.1182/blood-2008-06-163774 . 1932170 . free . 1765/19345 . free .
11. Lee SM, Tole S, Grove E, McMahon AP . A local Wnt-3a signal is required for development of the mammalian hippocampus . Development . 127 . 3 . 457–67 . February 2000 . 10.1242/dev.127.3.457 . 10631167 .
12. Uribe-Etxebarria V, García-Gallastegui P, Pérez-Garrastachu M, Casado-Andrés M, Irastorza I, Unda F, Ibarretxe G, Subirán N . 6 . Wnt-3a Induces Epigenetic Remodeling in Human Dental Pulp Stem Cells . Cells . 9 . 3 . E652 . March 2020 . 32156036 . 7140622 . 10.3390/cells9030652 . free .