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beta-Catenin-TCF/LEF signaling promotes steady-state and emergency granulopoiesis via G-CSF receptor upregulation
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SYSNO ASEP 0538141 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title beta-Catenin-TCF/LEF signaling promotes steady-state and emergency granulopoiesis via G-CSF receptor upregulation Author(s) Daněk, Petr (UMG-J)
Kardošová, Miroslava (UMG-J)
Janečková, Lucie (UMG-J)
Karkoulia, Eleni (UMG-J)
Vaníčková, Karolína (UMG-J)
Fabišik, Matěj (UMG-J)
Lozano-Asencio, C. (CZ)
Benoukraf, T. (CA)
Tirado-Magallanes, R. (SG)
Zhou, Q. (SG)
Burocziová, Monika (UMG-J)
Rahmatová, S. (CZ)
Pytlik, R. (CZ)
Brdička, Tomáš (UMG-J) RID
Tenen, D.G. (US)
Kořínek, Vladimír (UMG-J) RID
Alberich-Jorda, Meritxell (UMG-J) RIDNumber of authors 17 Source Title Blood. - : American Society of Hematology - ISSN 0006-4971
Roč. 136, č. 22 (2020), s. 2574-2587Number of pages 14 s. Publication form Online - E Language eng - English Country US - United States Keywords colony-stimulating-factor ; hematopoietic stem-cell ; wnt gene family ; self-renewal ; in-vitro ; granulocytic differentiation ; transcriptional activation ; progenitor cells ; binding ; impairs Subject RIV EB - Genetics ; Molecular Biology OECD category Biochemistry and molecular biology R&D Projects LM2015040 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2018126 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) ED2.1.00/19.0395 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) GA17-02177S GA ČR - Czech Science Foundation (CSF) Method of publishing Limited access Institutional support UMG-J - RVO:68378050 UT WOS 000594450900014 DOI 10.1182/blood.2019004664 Annotation The canonical Wnt signaling pathway is mediated by interaction of beta-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 beta-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 beta-catenin-TCF/LEF interaction. Disruption of the beta-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 and enhancer of CSF3R. Inhibition of 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 beta-catenin-TCF/LEF signaling in human CD34(+) cells reduced granulocytic differentiation, whereas its activation enhanced myelopoiesis. Altogether, our data indicate that the beta-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 beta-catenin signaling pathway in fine tuning the granulocytic production, opening venues for clinical intervention that require enhanced or reduced production of neutrophils. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2021 Electronic address https://ashpublications.org/blood/article-abstract/136/22/2574/463438/Catenin-TCF-LEF-signaling-promotes-steady-state?redirectedFrom=fulltext
Number of the records: 1