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Regulation of ciliary function by fibroblast growth factor signaling identifies FGFR3-related disorders achondroplasia and thanatophoric dysplasia as ciliopathies
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SYSNO ASEP 0489556 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Regulation of ciliary function by fibroblast growth factor signaling identifies FGFR3-related disorders achondroplasia and thanatophoric dysplasia as ciliopathies Author(s) Kunová Bosáková, M. (CZ)
Vařecha, M. (CZ)
Hampl, Marek (UZFG-Y) ORCID
Duran, I. (US)
Nita, A. (CZ)
Buchtová, Marcela (UZFG-Y) RID, ORCID
Dosedělová, Hana (UZFG-Y)
Machat, R. (CZ)
Xie, Y. (CN)
Ni, Z. (CN)
Martin, J. H. (US)
Chen, L. (CN)
Jansen, G. (NL)
Krakow, D. (US)
Krejčí, P. (CZ)Source Title Human Molecular Genetics. - : Oxford University Press - ISSN 0964-6906
Roč. 27, č. 6 (2018), s. 1093-1105Number of pages 13 s. Publication form Print - P Language eng - English Country GB - United Kingdom Keywords achondroplasia ; thanatophoric dysplasia Subject RIV EB - Genetics ; Molecular Biology OECD category Developmental biology R&D Projects EF15_003/0000460 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Institutional support UZFG-Y - RVO:67985904 UT WOS 000426838700013 EID SCOPUS 85043313766 DOI 10.1093/hmg/ddy031 Annotation Cilia project from almost every cell integrating extracellular cues with signaling pathways. Constitutive activation of FGFR3 signaling produces the skeletal disorders achondroplasia (ACH) and thanatophoric dysplasia (TD), but many of the molecular mechanisms underlying these phenotypes remain unresolved. Here, we report in vivo evidence for significantly shortened primary cilia in ACH and TD cartilage growth plates. Using in vivo and in vitro methodologies, our data demonstrate that transient versus sustained activation of FGF signaling correlated with different cilia consequences. Transient FGF pathway activation elongated cilia, while sustained activity shortened cilia. FGF signaling extended primary cilia via ERK MAP kinase and mTORC2 signaling, but not through mTORC1. Employing a GFP-tagged IFT20 construct to measure intraflagellar (IFT) speed in cilia, we showed that FGF signaling affected IFT velocities, as well as modulating cilia-based Hedgehog signaling. Our data integrate primary cilia into canonical FGF signal transduction and uncover a FGF-cilia pathway that needs consideration when elucidating the mechanisms of physiological and pathological FGFR function, or in the development of FGFR therapeutics. Workplace Institute of Animal Physiology and Genetics Contact Jana Zásmětová, knihovna@iapg.cas.cz, Tel.: 315 639 554 Year of Publishing 2019
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