beta-Catenin-TCF/LEF signaling promotes steady-state and emergency granulopoiesis via G-CSF receptor upregulation
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F20%3A00538141" target="_blank" >RIV/68378050:_____/20:00538141 - isvavai.cz</a>
Alternative codes found
RIV/00023736:_____/20:00013167
Result on the web
<a href="https://ashpublications.org/blood/article-abstract/136/22/2574/463438/Catenin-TCF-LEF-signaling-promotes-steady-state?redirectedFrom=fulltext" target="_blank" >https://ashpublications.org/blood/article-abstract/136/22/2574/463438/Catenin-TCF-LEF-signaling-promotes-steady-state?redirectedFrom=fulltext</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1182/blood.2019004664" target="_blank" >10.1182/blood.2019004664</a>
Alternative languages
Result language
angličtina
Original language name
beta-Catenin-TCF/LEF signaling promotes steady-state and emergency granulopoiesis via G-CSF receptor upregulation
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2020
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Blood
ISSN
0006-4971
e-ISSN
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Volume of the periodical
136
Issue of the periodical within the volume
22
Country of publishing house
US - UNITED STATES
Number of pages
14
Pages from-to
2574-2587
UT code for WoS article
000594450900014
EID of the result in the Scopus database
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