Tcf7L2
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Generation of neurons in the embryonic neocortex is a balanced process of proliferation and differentiation of neuronal progenitor cells. Canonical Wnt signalling is crucial for expansion of radial glial cells in the ventricular zone and for differentiation of intermediate progenitors in the subventricular zone. We detected abundant expression of two transcrtiption factors mediating canonical Wnt signalling, Tcf7L1 and Tcf7L2, in the ventricular zone of the embryonic neocortex. Conditional knock-out analysis showed that Tcf7L2, but not Tcf7L1, is the principal Wnt mediator important for maintenance of progenitor cell identity in the ventricular zone. In the absence of Tcf7L2, the Wnt activity is reduced, ventricular zone markers Pax6 and Sox2 are downregulated and the neuroepithelial structure is severed due to the loss of apical adherens junctions. This results in decreased proliferation of radial glial cells, the reduced number of intermediate progenitors in the subventricular zone and hypoplastic forebrain. Our data show that canonical Wnt signalling, which is essential for determining the neuroepithelial character of the neocortical ventricular zone, is mediated by Tcf7L2.
- MeSH
- buněčná diferenciace genetika MeSH
- chlorid-hydrogenuhličitanové antiportéry MeSH
- down regulace genetika MeSH
- embryo savčí MeSH
- hipokampus cytologie embryologie MeSH
- mutace genetika MeSH
- myši transgenní MeSH
- myši MeSH
- neokortex cytologie embryologie MeSH
- nervové kmenové buňky fyziologie MeSH
- neurogeneze fyziologie MeSH
- neuroglie MeSH
- neurony fyziologie MeSH
- počet buněk MeSH
- proliferace buněk genetika MeSH
- protein 2 podobný transkripčnímu faktoru 7 genetika metabolismus MeSH
- proteiny T-boxu metabolismus MeSH
- proteiny Wnt metabolismus MeSH
- retinální gangliové buňky fyziologie MeSH
- signální transdukce genetika MeSH
- transkripční faktory SOXB1 metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Úvod/Cieľ: Asociácia polymorfizmu génu transkripčného faktora TCF7L2 rs7903146 C/T s výskytom diabetu mellitu 2. typu (DM2) predstavuje doteraz najsilnejšiu opísanú asociáciu (zvýšenie rizika DM2 o 40 %). Asociácia pre tento polymorfizmus bola replikovaná vo viacerých svetových populáciách, avšak sila asociácie, ako aj frekvencia rizikovej alely T je rozdielna medzi populáciami. Cieľom štúdie bolo replikovať asociáciu TCF7L2 rs7903146 C/T s DM2 v populácii Slovenska a určiť frekvenciu rizikovej alely T. Metódy: U 538 pacientov s DM2 a 361 účastníkov s normálnou glukózovou toleranciou (kontroly) sme určili genotypy polymorfizmu TCF7L2 rs7903146 C/T metódou asymetrickej PCR s neznačenými oligonukleotidmi s analýzou meltingovej krivky. Antropometrické a laboratórne parametre boli vyšetrené štandardnými metódami. Výsledky: Frekvencia zriedkavejšej, rizikovej alely T bola vyššia v skupine DM2 v porovnaní s kontrolnou skupinou (30 % vz. 28 %), čo predstavovalo v log-aditívnom modeli signifikantné zvýšenie rizika per allelam skoro o 30 % (OR 1,29; 95 % KI 1,00 - 1,66; p = 0,048). Zastúpenie genotypu T/T bolo signifikantne vyššie v skupine pacientov s DM2 (11 %) v porovnaní s kontrolami (6 %) (59/538 vz. 21/361; p = 0,015) a po korekcii na vek, pohlavie a BMI bol genotyp T/T asociovaný s vyšším rizikom DM2 (OR 2,57; 95 % KI 1,40 - 4,73; p = 0,002) v porovnaní s nosičmi alely C (C/T + C/C). Záver: Replikovali sme asociáciu polymorfizmu TCF7L2 rs7903146 C/T s vyšším rizikom diabetu mellitu 2. typu v populácii Slovenska. Frekvencia rizikovej alely T a sila asociácie s DM2 sú v populácii Slovenska porovnateľné s inými kaukazoidnými populáciami.
Background/Aim: Polymorphism of the transcription factor gene TCF7L2 rs7903146 C/T has shown so far the strongest and best replicated association with type 2 diabetes (DM2), T-allele carrying 40 % increased risk. Although widely replicated, rs7903146 has shown marked variation in both frequency of the minor T-allele as well as the strength of association with DM2 among populations. Aim of this study was to replicate the association between TCF7L2 rs7903146 C/T and DM2 in the Slovakian population and to estimate frequency of the risk allele T. Methods: 538 DM2 patients and 361 subjects with normal glucose tolerance were genotyped for TCF7L2 rs7903146 C/T by assymetric PCR with unlabeled dyes and melting curve analysis. Anthropometric and biochemical examinations were performed by routine methods. Results: Minor, risk allele frequency (T) was higher among DM2 patients compared with controls (30 % vs. 28 %), which resulted in significant 30 % increased risk per T allele in the log-additive genetic model (OR 1,29; 95 % CI 1,00 - 1,66; p = 0,048). Genotype T/T was more prevalent among DM2 (11 %) than in controls (6 %) (59/538 vs. 21/361; p = 0,015). Adjusted for age, sex and BMI, genotype T/T was associated with increased risk of DM2 (OR 2,57; 95 %CI 1,40 - 4,73; p = 0,002) compared with C-allele carriers (C/T + C/C). Conclusion: We replicated association of TCF7L2 rs7903146 C/T with increased risk of type 2 diabetes in the Slovakian population. Both minor (risk) allele frequency (T) and the strength of association with DM2 is comparable with the other Caucasian populations.
The association of transcription factor 7-like 2 (TCF7L2) gene variants with the pathogenesis of T2D, gestational diabetes and polycystic ovary syndrome (PCOS) was examined. The study involved 1460 individuals: 347 T2D patients (D); 261 gestational diabetics (G); 147 offspring of T2D (O); 329 women with PCOS, and 376 controls (C). The SNPs: rs7901695; rs7903146; rs12255372 in the TCF7L2 gene were genotyped. Anthropometric and biochemical parameters, oGTT derived indices were assessed. In addition, free fatty acids (FFAs) were evaluated in 183 non-diabetic women. The CTT haplotype showed the strongest association with T2D with OR 1.57, p=0.0003. The frequency of the CTT/CTT haplotype was decreasing in following order: D 10.6, O 9.5, G 6.1, C 5.3 and PCOS 4.9 [%]. Among CTT carriers, significantly decreased levels of oGTT-stimulated insulin and C-peptide as well as proportions of fasting PUFAs were observed. The carriership of CTG/TCG was associated with gestational diabetes, OR 2.59, p=0.036. The association of TCF7L2 haplotypes with T2D and gestational diabetes but not with PCOS was confirmed. Novel association of TCF7L2 with FFAs composition was found.
- MeSH
- analýza rozptylu MeSH
- biologické markery krev MeSH
- diabetes mellitus 2. typu epidemiologie genetika krev MeSH
- dospělí MeSH
- fenotyp MeSH
- frekvence genu MeSH
- genetická predispozice k nemoci MeSH
- gestační diabetes epidemiologie genetika krev MeSH
- haplotypy MeSH
- hodnocení rizik MeSH
- jednonukleotidový polymorfismus MeSH
- kyseliny mastné neesterifikované krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- odds ratio MeSH
- protein 2 podobný transkripčnímu faktoru 7 genetika MeSH
- rizikové faktory MeSH
- rozdělení chí kvadrát MeSH
- senioři MeSH
- syndrom polycystických ovarií epidemiologie genetika krev MeSH
- těhotenství MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Geografické názvy
- Česká republika MeSH
Deriváty sulfonylurey a glinidy (meglitinidy) radíme medzi orálne inzulínové sekretagogá, pretože stimulujú sekréciu inzulínu z pankreatických β-buniek. Predpokladom ich účinku je zachovaná reziduálna sekrécia pankreatických β-buniek. V liečbe diabetu mellitu 2. typu (DM 2) sa využívajú už viac ako 50 rokov. Napriek ich celkovej efektivite boli pozorované značné interindividuálne rozdiely v liečebnej odpovedi, dispozícii lieku v organizme aj vo frekvencii nežiaducich účinkov. Okrem fenotypických rozdielov, ktoré spôsobujú uvedenú variabilitu, prispieva k nej aj rozdielne genetické pozadie pacientov. Pri skúmaní tejto zložky variability sa využívajú poznatky farmakogenomiky. Farmakogenomika sa zaoberá štúdiom závislosti medzi liečebnou odpoveďou pacienta na podaný liek a jeho genetickou informáciou. Ako prvá bola opísaná asociácia genetických polymorfizmov enzýmov metabolizujúcich deriváty sulfonylurey (izoenzým 2C9 cytochrómu P450 kódovaný génom CYP2C9). Novšie sa výskum upriamil na varianty génov kódujúcich cieľové molekuly pre jednotlivé sekretagogá, ako aj kandidátskych génov DM 2. Z týchto génov boli zatiaľ zistené asociácie terapeutického účinku inzulínových sekretagóg s polymorfizmami génu kódujúceho transkripčný faktor 7 podobný faktoru 2 (TCF7L2), ako aj génov kódujúcich bielkoviny tvoriace ATP-dependentný káliový kanál Kir6.2 – (gén KCNJ11) a sulfonylureový receptor 1 (SUR1 – gén ABCC8).
Sulphonylurea (SU) derivatives and glinines (meglitinides) we rate among oral insulin secretagogues, because they stimulate insulin secretion from pancreatic β-cells. The condition for their effect is preserved residual secretion of pancreatic β-cells. They have been already used in the treatment of diabetes mellitus 2 type (DM2) for more than over 50 years. Despite their overall effectiveness there were observed substantial interindividual differences in the treatment response, disposition of the drug in the organism and also in the frequency of adverse effects. Besides phenotypical differences which cause the stated variability, also different genetic background of patients contribute to it. The knowledge of pharmacogenetics is used in investigation of this variability component. Pharmacogenetics deals with the study of dependency between the treatment response of the patient to the administered drug and his genetic information. The association of genetic polymorphines of enzymes metobolising the derivatives of sulphonylurea (cytochrome-P450 isoenzyme 2C9 coded by the gene CYP2C9). Recently the research was oriented to variants of genes coding target molecules for particular secretagogues as well as candidate genes DM2. Until now the associations of therapeutic effect of insulin secretagogues with polymorphisms of the gene coding transcription factor 7 similar to the factor 2 (TCF7L2), as well as genes coding proteins creating ATP-dependent kalium channel Kir6.2 - (gene KCNJ11) and sulphonylurea receptor 1 (SUR1 - gene ABCC8) were found from these genes.
The canonical Wnt signaling pathway is mediated by interaction of β-catenin with the T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription factors and subsequent transcription activation of Wnt-target genes. In the hematopoietic system, the function of the pathway has been mainly investigated by rather unspecific genetic manipulations of β-catenin that yielded contradictory results. Here, we used a mouse expressing a truncated dominant negative form of the human TCF4 transcription factor (dnTCF4) that specifically abrogates β-catenin-TCF/LEF interaction. Disruption of the β-catenin-TCF/LEF interaction resulted in the accumulation of immature cells and reduced granulocytic differentiation. Mechanistically, dnTCF4 progenitors exhibited downregulation of the Csf3r gene, reduced granulocyte colony-stimulating factor (G-CSF) receptor levels, attenuation of downstream Stat3 phosphorylation after G-CSF treatment, and impaired G-CSF-mediated differentiation. Chromatin immunoprecipitation assays confirmed direct binding of TCF/LEF factors to the promoter and putative enhancer regions of CSF3R. Inhibition of β-catenin signaling compromised activation of the emergency granulopoiesis program, which requires maintenance and expansion of myeloid progenitors. Consequently, dnTCF4 mice were more susceptible to Candida albicans infection and more sensitive to 5-fluorouracil-induced granulocytic regeneration. Importantly, genetic and chemical inhibition of β-catenin-TCF/LEF signaling in human CD34+ cells reduced granulocytic differentiation, whereas its activation enhanced myelopoiesis. Altogether, our data indicate that the β-catenin-TCF/LEF complex directly regulates G-CSF receptor levels, and consequently controls proper differentiation of myeloid progenitors into granulocytes in steady-state and emergency granulopoiesis. Our results uncover a role for the β-catenin signaling pathway in fine tuning the granulocytic production, opening venues for clinical intervention that require enhanced or reduced production of neutrophils.
- MeSH
- beta-katenin genetika metabolismus MeSH
- Candida albicans MeSH
- granulocyty metabolismus MeSH
- kandidóza genetika metabolismus MeSH
- myelopoéza * MeSH
- myši transgenní MeSH
- myši MeSH
- protein 2 podobný transkripčnímu faktoru 7 metabolismus MeSH
- receptory faktoru stimulujícího kolonie biosyntéza genetika MeSH
- signální transdukce * MeSH
- transkripční faktory TCF genetika metabolismus MeSH
- upregulace * MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
