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

Studies have documented that the pathogenesis of autoimmune diabetes is influenced by the intake of gluten. Aims. To investigate the importance of gluten exposure during pregnancy and the subsequent development of autoimmune diabetes in offspring. Methods. Nonobese diabetic mice were divided into 7 groups to receive combinations of gluten-free and standard diet before, during, or after pregnancy. Diabetes incidence in offspring was followed in each group (n = 16-27) for 310 days. Insulitis score and intestinal expression of T-cell transcription factors (RT-QPCR) were evaluated in animals from the different diet groups. Results. If mothers were fed a gluten-free diet only during pregnancy, the development of autoimmune diabetes in offspring was almost completely prevented with an incidence reduction from 62.5% in gluten-consuming mice to 8.3% (p < 0.0001) in the gluten-free group. The islets of Langerhans were less infiltrated (p < 0.001) and the intestinal expression of RORγt (Th17) (p < 0.0001) reduced in mice whose mothers were Gluten-free during pregnancy. Conclusion. A gluten-free diet exclusively during pregnancy efficiently prevents autoimmune diabetes development in offspring and reduces insulitis and intestinal expression of RORγt (Th17).

• MeSH
• bezlepková dieta metody   MeSH
• diabetes mellitus 1. typu dietoterapie   imunologie   prevence a kontrola   MeSH
• jaderné receptory - podrodina 1, skupina F, člen 3 genetika   MeSH
• Langerhansovy ostrůvky imunologie   patologie   MeSH
• messenger RNA metabolismus   MeSH
• myši inbrední NOD MeSH
• myši MeSH
• pankreatitida imunologie   patologie   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• střeva metabolismus   MeSH
• těhotenství při diabetu dietoterapie   MeSH
• těhotenství MeSH
• transkripční faktory TCF genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The hypermethylated in cancer 1 (HIC1) gene is epigenetically inactivated in cancer, and in addition, the haploinsufficiency of HIC1 is linked to the development of human Miller-Dieker syndrome. HIC1 encodes a zinc-finger transcription factor that acts as a transcriptional repressor. Additionally, the HIC1 protein oligomerizes via the N-terminal BTB/POZ domain and forms discrete nuclear structures known as HIC1 bodies. Here, we provide evidence that HIC1 antagonizes the TCF/beta-catenin-mediated transcription in Wnt-stimulated cells. This appears to be due to the ability of HIC1 to associate with TCF-4 and to recruit TCF-4 and beta-catenin to the HIC1 bodies. As a result of the recruitment, both proteins are prevented from association with the TCF-binding elements of the Wnt-responsive genes. These data indicate that the intracellular amounts of HIC1 protein can modulate the level of the transcriptional stimulation of the genes regulated by canonical Wnt/beta-catenin signaling.

• MeSH
• beta-katenin genetika   metabolismus   MeSH
• buněčné jádro metabolismus   MeSH
• cytoskeletální proteiny genetika   metabolismus   MeSH
• DNA vazebné proteiny genetika   metabolismus   MeSH
• financování organizované MeSH
• genetická transkripce MeSH
• kultivační média speciální MeSH
• lidé MeSH
• myši MeSH
• promotorové oblasti (genetika) MeSH
• proteiny Wnt genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• RNA interference MeSH
• signální transdukce fyziologie   MeSH
• transkripční faktory Krüppel-like MeSH
• transkripční faktory TCF genetika   metabolismus   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH