TCF7L2

TCF7L2 is a transcription factor influencing the transcription of several genes thereby exerting a large variety of functions within the cell. It is a member of the TCF family that can form a bipartite transcription factor (β-catenin/TCF) alongside β-catenin. Bipartite transcription factors can have large effects on the Wnt signalling pathway. Stimulation of the Wnt signaling pathway leads to the association of β-catenin with BCL9, translocation to the nucleus, and association with TCF7L2,{{cite journal | vauthors = Lee JM, Dedhar S, Kalluri R, Thompson EW | title = The epithelial-mesenchymal transition: new insights in signaling, development, and disease | journal = The Journal of Cell Biology | volume = 172 | issue = 7 | pages = 973–981 | date = March 2006 | pmid = 16567498 | pmc = 2063755 | doi = 10.1083/jcb.200601018 }} which in turn results in the activation of Wnt target genes. The activation of the Wnt target genes specifically represses proglucagon synthesis in enteroendocrine cells. The repression of TCF7L2 using HMG-box repressor (HBP1) inhibits Wnt signalling. Therefore, TCF7L2 is an effector in the Wnt signalling pathway. TCF7L2's role in glucose metabolism is expressed in many tissues such as gut, brain, liver, and skeletal muscle. However, TCF7L2 does not directly regulate glucose metabolism in β-cells, but regulates glucose metabolism in pancreatic and liver tissues.{{cite journal | vauthors = Facchinello N, Tarifeño-Saldivia E, Grisan E, Schiavone M, Peron M, Mongera A, Ek O, Schmitner N, Meyer D, Peers B, Tiso N, Argenton F | title = Tcf7l2 plays pleiotropic roles in the control of glucose homeostasis, pancreas morphology, vascularization and regeneration | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 9605 | date = August 2017 | pmid = 28851992 | pmc = 5575064 | doi = 10.1038/s41598-017-09867-x | bibcode = 2017NatSR...7.9605F }} That said, TCF7L2 directly regulates the expression of multiple transcription factors, axon guidance cues, cell adhesion molecules and ion channels in the thalamus.{{cite journal | vauthors = Lipiec MA, Bem J, Koziński K, Chakraborty C, Urban-Ciećko J, Zajkowski T, Dąbrowski M, Szewczyk ŁM, Toval A, Ferran JL, Nagalski A, Wiśniewska MB | title = TCF7L2 regulates postmitotic differentiation programmes and excitability patterns in the thalamus | journal = Development | volume = 147 | issue = 16 | pages = dev.190181 | date = August 2020 | pmid = 32675279 | pmc = 7473649 | doi = 10.1242/dev.190181 }}

The TCF7L2 gene encoding the TCF7L2 transcription factor, exhibits multiple functions through its polymorphisms and thus, is known as a pleiotropic gene. Type 2 diabetes T2DM susceptibility is exhibited in carriers of TCF7L2 rs7903146C>T{{cite journal | vauthors = Chen Y, Zhao Y, Li YB, Wang YJ, Zhang GZ | title = Detection of SNPs of T2DM susceptibility genes by a ligase detection reaction-fluorescent nanosphere technique | journal = Analytical Biochemistry | volume = 540-541 | issue = Supplement C | pages = 38–44 | date = January 2018 | pmid = 29128291 | doi = 10.1016/j.ab.2017.11.003 }}{{cite journal | vauthors = Zhu L, Xie Z, Lu J, Hao Q, Kang M, Chen S, Tang W, Ding H, Chen Y, Liu C, Wu H | title = TCF7L2 rs290481 T>C polymorphism is associated with an increased risk of type 2 diabetes mellitus and fasting plasma glucose level | journal = Oncotarget | volume = 8 | issue = 44 | pages = 77000–77008 | date = September 2017 | pmid = 29100364 | pmc = 5652758 | doi = 10.18632/oncotarget.20300 }} and rs290481T>C polymorphisms. TCF7L2 rs290481T>C polymorphism, however, has shown no significant correlation to the susceptibility to gestational diabetes mellitus (GDM) in a Chinese Han population, whereas the T alleles of rs7903146 and rs1799884{{cite journal | vauthors = Zhang C, Bao W, Rong Y, Yang H, Bowers K, Yeung E, Kiely M | title = Genetic variants and the risk of gestational diabetes mellitus: a systematic review | journal = Human Reproduction Update | volume = 19 | issue = 4 | pages = 376–390 | date = 2013-05-19 | pmid = 23690305 | pmc = 3682671 | doi = 10.1093/humupd/dmt013 }} increase susceptibility to GDM in the Chinese Han population. The difference in effects of the different polymorphisms of the gene indicate that the gene is indeed pleiotropic.

The TCF7L2 gene, encoding the TCF7L2 protein, is located on chromosome 10q25.2-q25.3. The gene contains 19 exons. Of the 19 exons, 5 are alternative. The TCF7L2 protein contains 619 amino acids and its molecular mass is 67919 Da.{{Cite web|url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=TCF7L2|title=TCF7L2 Gene - GeneCards {{!}} TF7L2 Protein {{!}} TF7L2 Antibody | work = GeneCards Human Gene Database |access-date=2017-11-30}} TCF7L2's secondary structure is a helix-turn-helix structure.{{Cite web|url=https://www.uniprot.org/uniprot/Q9NQB0|title=TCF7L2 - Transcription factor 7-like 2 - Homo sapiens (Human) - TCF7L2 gene & protein|website=www.uniprot.org|language=en|access-date=2017-11-30}}

TCF7L2 is primarily expressed in brain (mainly in the diencephalon, including especially high in the thalamus{{cite journal | vauthors = Nagalski A, Irimia M, Szewczyk L, Ferran JL, Misztal K, Kuznicki J, Wisniewska MB | title = Postnatal isoform switch and protein localization of LEF1 and TCF7L2 transcription factors in cortical, thalamic, and mesencephalic regions of the adult mouse brain | journal = Brain Structure & Function | volume = 218 | issue = 6 | pages = 1531–1549 | date = November 2013 | pmid = 23152144 | pmc = 3825142 | doi = 10.1007/s00429-012-0474-6 }}{{cite journal | vauthors = Murray KD, Rubin CM, Jones EG, Chalupa LM | title = Molecular correlates of laminar differences in the macaque dorsal lateral geniculate nucleus | journal = The Journal of Neuroscience | volume = 28 | issue = 46 | pages = 12010–12022 | date = November 2008 | pmid = 19005066 | pmc = 2613947 | doi = 10.1523/JNEUROSCI.3800-08.2008 }}), liver, intestine and fat cells. It does not primarily operate in the β-cells in the pancreas.{{cite journal | vauthors = Nobrega MA | title = TCF7L2 and glucose metabolism: time to look beyond the pancreas | journal = Diabetes | volume = 62 | issue = 3 | pages = 706–708 | date = March 2013 | pmid = 23431017 | pmc = 3581232 | doi = 10.2337/db12-1418 }}

Several single nucleotide polymorphisms within the TCF7L2 gene have been associated with type 2 diabetes. Studies conducted by Ravindranath Duggirala and Michael Stern at The University of Texas Health Science Center at San Antonio were the first to identify strong linkage for type 2 diabetes at a region on Chromosome 10 in Mexican Americans {{cite journal | vauthors = Duggirala R, Blangero J, Almasy L, Dyer TD, Williams KL, Leach RJ, O'Connell P, Stern MP | title = Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans | journal = American Journal of Human Genetics | volume = 64 | issue = 4 | pages = 1127–1140 | date = April 1999 | pmid = 10090898 | pmc = 1377837 | doi = 10.1086/302316 }} This signal was later refined by Struan Grant and colleagues at DeCODE genetics and isolated to the TCF7L2 gene.{{cite journal | vauthors = Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, Stefansson K | title = Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes | journal = Nature Genetics | volume = 38 | issue = 3 | pages = 320–323 | date = March 2006 | pmid = 16415884 | doi = 10.1038/ng1732 | s2cid = 28825825 }} The molecular and physiological mechanisms underlying the association of TCF7L2 with type 2 diabetes are under active investigation, but it is likely that TCF7L2 has important biological roles in multiple metabolic tissues, including the pancreas, liver and adipose tissue.{{cite journal | vauthors = Jin T | title = Current Understanding on Role of the Wnt Signaling Pathway Effector TCF7L2 in Glucose Homeostasis | journal = Endocrine Reviews | volume = 37 | issue = 3 | pages = 254–277 | date = June 2016 | pmid = 27159876 | doi = 10.1210/er.2015-1146 | doi-access = free }} TCF7L2 polymorphisms can increase susceptibility to type 2 diabetes by decreasing the production of glucagon-like peptide-1 (GLP-1).

TCF7L2 modulates pancreatic islet β-cell function strongly implicating its significant association with GDM risk. T alleles of rs7903146 and rs1799884 TCF7L2 polymorphisms increase susceptibility to GDM in the Chinese Han population.

TCF7L2 plays a role in colorectal cancer. A frameshift mutation of TCF7L2 provided evidence that TCF7L2 is implicated in colorectal cancer.{{cite journal | vauthors = Slattery ML, Folsom AR, Wolff R, Herrick J, Caan BJ, Potter JD | title = Transcription factor 7-like 2 polymorphism and colon cancer | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 17 | issue = 4 | pages = 978–982 | date = April 2008 | pmid = 18398040 | pmc = 2587179 | doi = 10.1158/1055-9965.EPI-07-2687 }}{{cite journal | vauthors = Hazra A, Fuchs CS, Chan AT, Giovannucci EL, Hunter DJ | title = Association of the TCF7L2 polymorphism with colorectal cancer and adenoma risk | journal = Cancer Causes & Control | volume = 19 | issue = 9 | pages = 975–980 | date = November 2008 | pmid = 18478343 | pmc = 2719293 | doi = 10.1007/s10552-008-9164-3 }} The silencing of TCF7L2 in KM12 colorectal cancer cells provided evidence that TCF7L2 played a role in proliferation and metastasis of cancer cells in colorectal cancer.

Variants of the gene are most likely involved in many other cancer types.{{cite journal | vauthors = Tang W, Dodge M, Gundapaneni D, Michnoff C, Roth M, Lum L | title = A genome-wide RNAi screen for Wnt/beta-catenin pathway components identifies unexpected roles for TCF transcription factors in cancer | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 28 | pages = 9697–9702 | date = July 2008 | pmid = 18621708 | pmc = 2453074 | doi = 10.1073/pnas.0804709105 | doi-access = free | bibcode = 2008PNAS..105.9697T }} TCF7L2 is indirectly involved in prostate cancer through its role in activating the PI3K/Akt pathway, a pathway involved in prostate cancer.{{cite journal | vauthors = Sun P, Xiong H, Kim TH, Ren B, Zhang Z | title = Positive inter-regulation between beta-catenin/T cell factor-4 signaling and endothelin-1 signaling potentiates proliferation and survival of prostate cancer cells | journal = Molecular Pharmacology | volume = 69 | issue = 2 | pages = 520–531 | date = February 2006 | pmid = 16291872 | doi = 10.1124/mol.105.019620 | s2cid = 10148857 }}

Single nucleotide polymorphisms (SNPs) in TCF7L2 gene have shown an increase in susceptibility to schizophrenia in Arab, European and Chinese Han populations.{{citation needed|date=November 2020}} In the Chinese Han population, SNP rs12573128 in TCF7L2 is the variant that was associated with an increase in schizophrenia risk. This marker is used as a pre-diagnostic marker for schizophrenia. TCF7L2 has also been reported as a risk gene in autism spectrum disorder{{Cite web |title=SFARI Gene Database - TCF7L2 |url=https://gene.sfari.org/database/human-gene/TCF7L2 |access-date=2022-07-16 |language=en-US}} and has been linked to it in recent large-scale genetic studies.

The mechanism behind TCF7L2's involvement in the emergence of neurodevelopmental disorders is not fully understood, as there have been few studies characterizing its role in brain development in detail. It was shown that during embryogenesis TCF7L2 is involved in the development of fish-specific habenula asymmetry in Danio rerio,{{cite journal | vauthors = Beretta CA, Dross N, Bankhead P, Carl M | title = The ventral habenulae of zebrafish develop in prosomere 2 dependent on Tcf7l2 function | journal = Neural Development | volume = 8 | issue = 1 | pages = 19 | date = September 2013 | pmid = 24067090 | pmc = 3827927 | doi = 10.1186/1749-8104-8-19 | doi-access = free }}{{cite journal | vauthors = Hüsken U, Stickney HL, Gestri G, Bianco IH, Faro A, Young RM, Roussigne M, Hawkins TA, Beretta CA, Brinkmann I, Paolini A, Jacinto R, Albadri S, Dreosti E, Tsalavouta M, Schwarz Q, Cavodeassi F, Barth AK, Wen L, Zhang B, Blader P, Yaksi E, Poggi L, Zigman M, Lin S, Wilson SW, Carl M | title = Tcf7l2 is required for left-right asymmetric differentiation of habenular neurons | journal = Current Biology | volume = 24 | issue = 19 | pages = 2217–2227 | date = October 2014 | pmid = 25201686 | pmc = 4194317 | doi = 10.1016/j.cub.2014.08.006 | bibcode = 2014CBio...24.2217H }} and that the dominant negative TCF7L2 isoform influences cephalic separation in the embryo by inhibiting the posteriorizing effect of the Wnt pathway.{{cite journal | vauthors = Vacik T, Stubbs JL, Lemke G | title = A novel mechanism for the transcriptional regulation of Wnt signaling in development | journal = Genes & Development | volume = 25 | issue = 17 | pages = 1783–1795 | date = September 2011 | pmid = 21856776 | pmc = 3175715 | doi = 10.1101/gad.17227011 }} It was also shown that in Tcf7l2 knockout mice the number of proliferating cells in cortical neural progenitor cells is reduced.{{cite journal | vauthors = Chodelkova O, Masek J, Korinek V, Kozmik Z, Machon O | title = Tcf7L2 is essential for neurogenesis in the developing mouse neocortex | journal = Neural Development | volume = 13 | issue = 1 | pages = 8 | date = May 2018 | pmid = 29751817 | pmc = 5946422 | doi = 10.1186/s13064-018-0107-8 | doi-access = free }} In contrast, no such effect was found in the midbrain.{{cite journal | vauthors = Lee M, Yoon J, Song H, Lee B, Lam DT, Yoon J, Baek K, Clevers H, Jeong Y | title = Tcf7l2 plays crucial roles in forebrain development through regulation of thalamic and habenular neuron identity and connectivity | journal = Developmental Biology | volume = 424 | issue = 1 | pages = 62–76 | date = April 2017 | pmid = 28219675 | doi = 10.1016/j.ydbio.2017.02.010 | doi-access = free }}

More recently it was shown that TCF7L2 plays a crucial role in both the embryonic development and postnatal maturation of the thalamus through direct and indirect regulation of many genes previously reported to be important for both processes. In late gestation TCF7L2 regulates the expression of many thalamus-enriched transcription factors (e.g. Foxp2, Rora, Mef2a, Lef1, Prox1), axon guidance molecules (e.g. Epha1, Epha4, Ntng1, Epha8) and cell adhesion molecules (e.g. Cdh6, Cdh8, Cdhr1). Accordingly, a total knockout of Tcf7l2 in mice leads to improper growth of thalamocortical axons, changed anatomy and improper sorting of the cells in the thalamo-habenular region. In the early postnaral period TCF7L2 starts to regulate the expression of many genes necessary for the acquisition of characteristic excitability patterns in the thalamus, mainly ion channels, neurotransmitters and their receptors and synaptic vescicle proteins (e.g. Cacna1g, Kcnc2, Slc17a7, Grin2b), and an early postnatal knockout of Tcf7l2 in mouse thalamus leads to significant reduction in the number and frequency of action potentials generated by the thalamocortical neurons. The mechanism that leads to the change in TCF7L2 target genes between gestation and early postnatal period is unknown. It is likely that a perinatal change in the proportion of TCF7L2 isoforms expressed in the thalamus is partially responsible. Abnormalities in the anatomy of the thalamus and the activity of its connections to the cerebral cortex are frequently detected in patients with schizophrenia {{cite journal | vauthors = de Zwarte SM, Brouwer RM, Tsouli A, Cahn W, Hillegers MH, Hulshoff Pol HE, Kahn RS, van Haren NE | title = Running in the Family? Structural Brain Abnormalities and IQ in Offspring, Siblings, Parents, and Co-twins of Patients with Schizophrenia | journal = Schizophrenia Bulletin | volume = 45 | issue = 6 | pages = 1209–1217 | date = October 2019 | pmid = 30597053 | pmc = 6811835 | doi = 10.1093/schbul/sby182 }}{{cite journal | vauthors = Giraldo-Chica M, Woodward ND | title = Review of thalamocortical resting-state fMRI studies in schizophrenia | journal = Schizophrenia Research | volume = 180 | pages = 58–63 | date = February 2017 | pmid = 27531067 | pmc = 5297399 | doi = 10.1016/j.schres.2016.08.005 | series = Pathologies of the Thalamus in Schizophrenia }}{{cite journal | vauthors = Hua J, Blair NI, Paez A, Choe A, Barber AD, Brandt A, Lim IA, Xu F, Kamath V, Pekar JJ, van Zijl PC, Ross CA, Margolis RL | title = Altered functional connectivity between sub-regions in the thalamus and cortex in schizophrenia patients measured by resting state BOLD fMRI at 7T | journal = Schizophrenia Research | volume = 206 | pages = 370–377 | date = April 2019 | pmid = 30409697 | pmc = 6500777 | doi = 10.1016/j.schres.2018.10.016 }}{{cite journal | vauthors = van Erp TG, Walton E, Hibar DP, Schmaal L, Jiang W, Glahn DC, Pearlson GD, Yao N, Fukunaga M, Hashimoto R, Okada N, Yamamori H, Bustillo JR, Clark VP, Agartz I, Mueller BA, Cahn W, de Zwarte SM, Hulshoff Pol HE, Kahn RS, Ophoff RA, van Haren NE, Andreassen OA, Dale AM, Doan NT, Gurholt TP, Hartberg CB, Haukvik UK, Jørgensen KN, Lagerberg TV, Melle I, Westlye LT, Gruber O, Kraemer B, Richter A, Zilles D, Calhoun VD, Crespo-Facorro B, Roiz-Santiañez R, Tordesillas-Gutiérrez D, Loughland C, Carr VJ, Catts S, Cropley VL, Fullerton JM, Green MJ, Henskens FA, Jablensky A, Lenroot RK, Mowry BJ, Michie PT, Pantelis C, Quidé Y, Schall U, Scott RJ, Cairns MJ, Seal M, Tooney PA, Rasser PE, Cooper G, Shannon Weickert C, Weickert TW, Morris DW, Hong E, Kochunov P, Beard LM, Gur RE, Gur RC, Satterthwaite TD, Wolf DH, Belger A, Brown GG, Ford JM, Macciardi F, Mathalon DH, O'Leary DS, Potkin SG, Preda A, Voyvodic J, Lim KO, McEwen S, Yang F, Tan Y, Tan S, Wang Z, Fan F, Chen J, Xiang H, Tang S, Guo H, Wan P, Wei D, Bockholt HJ, Ehrlich S, Wolthusen RP, King MD, Shoemaker JM, Sponheim SR, De Haan L, Koenders L, Machielsen MW, van Amelsvoort T, Veltman DJ, Assogna F, Banaj N, de Rossi P, Iorio M, Piras F, Spalletta G, McKenna PJ, Pomarol-Clotet E, Salvador R, Corvin A, Donohoe G, Kelly S, Whelan CD, Dickie EW, Rotenberg D, Voineskos AN, Ciufolini S, Radua J, Dazzan P, Murray R, Reis Marques T, Simmons A, Borgwardt S, Egloff L, Harrisberger F, Riecher-Rössler A, Smieskova R, Alpert KI, Wang L, Jönsson EG, Koops S, Sommer IE, Bertolino A, Bonvino A, Di Giorgio A, Neilson E, Mayer AR, Stephen JM, Kwon JS, Yun JY, Cannon DM, McDonald C, Lebedeva I, Tomyshev AS, Akhadov T, Kaleda V, Fatouros-Bergman H, Flyckt L, Busatto GF, Rosa PG, Serpa MH, Zanetti MV, Hoschl C, Skoch A, Spaniel F, Tomecek D, Hagenaars SP, McIntosh AM, Whalley HC, Lawrie SM, Knöchel C, Oertel-Knöchel V, Stäblein M, Howells FM, Stein DJ, Temmingh HS, Uhlmann A, Lopez-Jaramillo C, Dima D, McMahon A, Faskowitz JI, Gutman BA, Jahanshad N, Thompson PM, Turner JA | title = Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium | journal = Biological Psychiatry | volume = 84 | issue = 9 | pages = 644–654 | date = November 2018 | pmid = 29960671 | pmc = 6177304 | doi = 10.1016/j.biopsych.2018.04.023 }} and autism.{{cite journal | vauthors = Ayub R, Sun KL, Flores RE, Lam VT, Jo B, Saggar M, Fung LK | title = Thalamocortical connectivity is associated with autism symptoms in high-functioning adults with autism and typically developing adults | journal = Translational Psychiatry | volume = 11 | issue = 1 | pages = 93 | date = February 2021 | pmid = 33536431 | pmc = 7859407 | doi = 10.1038/s41398-021-01221-0 }}{{cite journal | vauthors = Schuetze M, Park MT, Cho IY, MacMaster FP, Chakravarty MM, Bray SL | title = Morphological Alterations in the Thalamus, Striatum, and Pallidum in Autism Spectrum Disorder | journal = Neuropsychopharmacology | volume = 41 | issue = 11 | pages = 2627–2637 | date = October 2016 | pmid = 27125303 | pmc = 5026732 | doi = 10.1038/npp.2016.64 }}{{cite journal | vauthors = Tomasi D, Volkow ND | title = Reduced Local and Increased Long-Range Functional Connectivity of the Thalamus in Autism Spectrum Disorder | journal = Cerebral Cortex | volume = 29 | issue = 2 | pages = 573–585 | date = February 2019 | pmid = 29300843 | pmc = 6319176 | doi = 10.1093/cercor/bhx340 }}{{cite journal | vauthors = Woodward ND, Giraldo-Chica M, Rogers B, Cascio CJ | title = Thalamocortical dysconnectivity in autism spectrum disorder: An analysis of the Autism Brain Imaging Data Exchange | journal = Biological Psychiatry. Cognitive Neuroscience and Neuroimaging | volume = 2 | issue = 1 | pages = 76–84 | date = January 2017 | pmid = 28584881 | pmc = 5455796 | doi = 10.1016/j.bpsc.2016.09.002 }} Such abnormalities could arise from developmental aberrations in patients with unfavorable mutations of TCF7L2, further strengthening the link between TCF7L2 and neurodevelopmental disorders.

TCF7L2 is downstream of the WNT/β-catenin pathways. The activation of the WNT/β-catenin pathways have been associated demyelination in multiple sclerosis. TCF7L2 is unregulated during early remyelination, leading scientists to believe that it is involved in remyelination. TCF7L2 could act in dependence or independent of the WNT/β-catenin pathways.{{cite journal | vauthors = Vallée A, Vallée JN, Guillevin R, Lecarpentier Y | title = Interactions Between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma on Neuroinflammation, Demyelination, and Remyelination in Multiple Sclerosis | journal = Cellular and Molecular Neurobiology | volume = 38 | issue = 4 | pages = 783–795 | date = May 2018 | pmid = 28905149 | doi = 10.1007/s10571-017-0550-9 | s2cid = 4620853 | pmc = 11482031 }}

Model organisms have been used in the study of TCF7L2 function. A conditional knockout mouse line called Tcf7l2^{tm1a(EUCOMM)Wtsi} was generated at the Wellcome Trust Sanger Institute.{{cite journal |title=The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice | vauthors = Gerdin AK |year=2010 |journal=Acta Ophthalmologica|volume=88 |pages=925–7|doi=10.1111/j.1755-3768.2010.4142.x | s2cid = 85911512 }} Male and female animals underwent a standardized phenotypic screen{{cite web |url=http://www.mousephenotype.org/data/search?q=Tcf7l2#fq=*:*&facet=gene |title=International Mouse Phenotyping Consortium}} to determine the effects of deletion.{{cite journal | vauthors = Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–342 | date = June 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }}{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–263 | date = June 2011 | pmid = 21677718 | doi = 10.1038/474262a | doi-access = free }}{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = January 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 | s2cid = 18872015 | doi-access = free }}{{cite journal | vauthors = White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP | title = Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes | journal = Cell | volume = 154 | issue = 2 | pages = 452–464 | date = July 2013 | pmid = 23870131 | pmc = 3717207 | doi = 10.1016/j.cell.2013.06.022 }} Additional screens performed: - In-depth immunological phenotyping{{cite web |url= http://www.immunophenotyping.org/data/search?keys=Tcf7l2&field_gene_construct_tid=All |title= Infection and Immunity Immunophenotyping (3i) Consortium }}{{Dead link|date=July 2024 |bot=InternetArchiveBot |fix-attempted=yes }}

Variations of the protein encoding gene are found in rats, zebra fish, drosophila, and budding yeast.{{Cite web|url=http://marrvel.org/search/gene/TCF7L2|title=MARRVEL: Search Result|website=marrvel.org|access-date=2017-11-30}} Therefore, all of those organisms can be used as model organisms in the study of TCF7L2 function. {{clear|left}}

TCF7L2 is the symbol officially approved by the HUGO Gene Nomenclature Committee for the Transcription Factor 7-Like 2 gene.

• TCF/LEF family

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{{Reflist}}

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• {{cite journal | vauthors = Barker N, Huls G, Korinek V, Clevers H | title = Restricted high level expression of Tcf-4 protein in intestinal and mammary gland epithelium | journal = The American Journal of Pathology | volume = 154 | issue = 1 | pages = 29–35 | date = January 1999 | pmid = 9916915 | pmc = 1853446 | doi = 10.1016/S0002-9440(10)65247-9 }}
• {{cite journal | vauthors = Omer CA, Miller PJ, Diehl RE, Kral AM | title = Identification of Tcf4 residues involved in high-affinity beta-catenin binding | journal = Biochemical and Biophysical Research Communications | volume = 256 | issue = 3 | pages = 584–590 | date = March 1999 | pmid = 10080941 | doi = 10.1006/bbrc.1999.0379 }}
• {{cite journal | vauthors = Giannini AL, Vivanco MM, Kypta RM | title = Analysis of beta-catenin aggregation and localization using GFP fusion proteins: nuclear import of alpha-catenin by the beta-catenin/Tcf complex | journal = Experimental Cell Research | volume = 255 | issue = 2 | pages = 207–220 | date = March 2000 | pmid = 10694436 | doi = 10.1006/excr.1999.4785 }}
• {{cite journal | vauthors = Duval A, Busson-Leconiat M, Berger R, Hamelin R | title = Assignment of the TCF-4 gene (TCF7L2) to human chromosome band 10q25.3 | journal = Cytogenetics and Cell Genetics | volume = 88 | issue = 3–4 | pages = 264–265 | year = 2000 | pmid = 10828605 | doi = 10.1159/000015534 | s2cid = 13148464 }}
• {{cite journal | vauthors = Duval A, Rolland S, Tubacher E, Bui H, Thomas G, Hamelin R | title = The human T-cell transcription factor-4 gene: structure, extensive characterization of alternative splicings, and mutational analysis in colorectal cancer cell lines | journal = Cancer Research | volume = 60 | issue = 14 | pages = 3872–3879 | date = July 2000 | pmid = 10919662 }}
• {{cite journal | vauthors = Brantjes H, Roose J, van De Wetering M, Clevers H | title = All Tcf HMG box transcription factors interact with Groucho-related co-repressors | journal = Nucleic Acids Research | volume = 29 | issue = 7 | pages = 1410–1419 | date = April 2001 | pmid = 11266540 | pmc = 31284 | doi = 10.1093/nar/29.7.1410 }}
• {{cite journal | vauthors = Palacino JJ, Murphy MP, Murayama O, Iwasaki K, Fujiwara M, Takashima A, Golde TE, Wolozin B | title = Presenilin 1 regulates beta-catenin-mediated transcription in a glycogen synthase kinase-3-independent fashion | journal = The Journal of Biological Chemistry | volume = 276 | issue = 42 | pages = 38563–38569 | date = October 2001 | pmid = 11504726 | doi = 10.1074/jbc.M105376200 | doi-access = free }}
• {{cite journal | vauthors = Graham TA, Ferkey DM, Mao F, Kimelman D, Xu W | title = Tcf4 can specifically recognize beta-catenin using alternative conformations | journal = Nature Structural Biology | volume = 8 | issue = 12 | pages = 1048–1052 | date = December 2001 | pmid = 11713475 | doi = 10.1038/nsb718 | s2cid = 33878077 }}
• {{cite journal | vauthors = Poy F, Lepourcelet M, Shivdasani RA, Eck MJ | title = Structure of a human Tcf4-beta-catenin complex | journal = Nature Structural Biology | volume = 8 | issue = 12 | pages = 1053–1057 | date = December 2001 | pmid = 11713476 | doi = 10.1038/nsb720 | s2cid = 24798619 }}
• {{cite journal | vauthors = Thiele A, Wasner M, Müller C, Engeland K, Hauschildt S | title = Regulation and possible function of beta-catenin in human monocytes | journal = Journal of Immunology | volume = 167 | issue = 12 | pages = 6786–6793 | date = December 2001 | pmid = 11739494 | doi = 10.4049/jimmunol.167.12.6786 | doi-access = free }}
• {{cite journal | vauthors = Marchenko GN, Marchenko ND, Leng J, Strongin AY | title = Promoter characterization of the novel human matrix metalloproteinase-26 gene: regulation by the T-cell factor-4 implies specific expression of the gene in cancer cells of epithelial origin | journal = The Biochemical Journal | volume = 363 | issue = Pt 2 | pages = 253–262 | date = April 2002 | pmid = 11931652 | pmc = 1222473 | doi = 10.1042/0264-6021:3630253 }}
• {{cite journal | vauthors = Leung JY, Kolligs FT, Wu R, Zhai Y, Kuick R, Hanash S, Cho KR, Fearon ER | title = Activation of AXIN2 expression by beta-catenin-T cell factor. A feedback repressor pathway regulating Wnt signaling | journal = The Journal of Biological Chemistry | volume = 277 | issue = 24 | pages = 21657–21665 | date = June 2002 | pmid = 11940574 | doi = 10.1074/jbc.M200139200 | doi-access = free }}

{{refend}}

• TCF7L2 here called TCF4 features on this Wnt pathway web site: [http://www.stanford.edu/~rnusse/pathways/cell2.html Wnt signalling molecules] [http://www.stanford.edu/~rnusse/axindshtcf/tcf2.html TCFs]
• Structure determination of TCF7L2: [http://www.rcsb.org/pdb/explore.do?structureId=2GL7 PDB entry 2GL7] and related publication on [https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=pubmed&term=Crystal%20Structure%20of%20a%20beta-Catenin/BCL9/Tcf4%20Complex PubMed]
• PubMed GeneRIFs (summaries of related scientific publications) - [https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=gene_full_report&db=gene&cmd=Display&dopt=gene_pubmed_rif&from_uid=6934]
• Weizmann Institute GeneCard for [https://www.genecards.org/cgi-bin/carddisp.pl?gene=TCF7L2&search=tcf7l2 TCF7L2]
• {{PDBe-KB2|Q9NQB0|Transcription factor 7-like 2}}

{{PDB Gallery|geneid=6934}}

{{Signaling proteins}}

{{Transcription factors|g4}}

Category:Transcription factors

Category:Signal transduction

Category:Gene expression