Regulation of ciliary function by fibroblast growth factor
signaling identifies FGFR3-related disorders achondroplasia and
thanatophoric dysplasia as ciliopathies

J 2018

Regulation of ciliary function by fibroblast growth factor signaling identifies FGFR3-related disorders achondroplasia and thanatophoric dysplasia as ciliopathies

BOSÁKOVÁ, Michaela, Miroslav VAŘECHA, Marek HAMPL, Ivan DURAN, Alexandru NITĂ et. al.

Basic information

Original name

Regulation of ciliary function by fibroblast growth factor signaling identifies FGFR3-related disorders achondroplasia and thanatophoric dysplasia as ciliopathies

Authors

BOSÁKOVÁ, Michaela (203 Czech Republic, belonging to the institution), Miroslav VAŘECHA (203 Czech Republic, belonging to the institution), Marek HAMPL (203 Czech Republic, belonging to the institution), Ivan DURAN (840 United States of America), Alexandru NITĂ (642 Romania, belonging to the institution), Marcela BUCHTOVÁ (203 Czech Republic, belonging to the institution), Hana DOSEDELOVA (203 Czech Republic), Radek MACHÁT (203 Czech Republic, belonging to the institution), Yangli XIE (156 China), Zhenhong NI (156 China), Jorge H. MARTIN (156 China), Lin CHEN (156 China), Gert JANSEN (528 Netherlands), Deborah KRAKOW (840 United States of America) and Pavel KREJČÍ (203 Czech Republic, guarantor, belonging to the institution)

Edition

Human molecular genetics, OXFORD, OXFORD UNIV PRESS, 2018, 0964-6906

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 4.544

RIV identification code

RIV/00216224:14110/18:00101656

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1093/hmg/ddy031

UT WoS

000426838700013

Keywords in English

ciliary function; fibroblast growth factor; FGFR3

Abstract

V originále

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.

Links

GA15-23033S, research and development project

Name: Úloha sekrece FGF2 ve fyziologii lidských pluripotentních kmenových buněk

Investor: Czech Science Foundation

GA17-09525S, research and development project

Name: Neobvyklé signální dráhy lidských receptorových tyrozinových kináz

Investor: Czech Science Foundation

LH15231, research and development project

Name: Nové mechanismy vzniku fatálních kostních ciliopatií u člověka

Investor: Ministry of Education, Youth and Sports of the CR

NV15-33232A, research and development project

Name: Identifikace nových možností léčby achondroplásie prostřednictvím analýzy interakce FGFR3 a adaptérového proteinu Frs2

NV15-34405A, research and development project

Name: Identifikace nových možností léčby chronické myeloidní leukémie pomocí systematické analýzy interaktomu proteinu BCR-ABL

ROZV/25/LF/2017, interní kód MU

Name: LF - Příspěvek na IP 2017

Investor: Ministry of Education, Youth and Sports of the CR, Internal development projects

Citovat

BOSÁKOVÁ, Michaela, Miroslav VAŘECHA, Marek HAMPL, Ivan DURAN, Alexandru NITĂ, Marcela BUCHTOVÁ, Hana DOSEDELOVA, Radek MACHÁT, Yangli XIE, Zhenhong NI, Jorge H. MARTIN, Lin CHEN, Gert JANSEN, Deborah KRAKOW and Pavel KREJČÍ. Regulation of ciliary function by fibroblast growth factor signaling identifies FGFR3-related disorders achondroplasia and thanatophoric dysplasia as ciliopathies. Human molecular genetics. OXFORD: OXFORD UNIV PRESS, 2018, vol. 27, No 6, p. 1093-1105. ISSN 0964-6906. Available from: https://dx.doi.org/10.1093/hmg/ddy031.

@article{1490536,
   author = {Bosáková, Michaela and Vařecha, Miroslav and Hampl, Marek and Duran, Ivan and Nită, Alexandru and Buchtová, Marcela and Dosedelova, Hana and Machát, Radek and Xie, Yangli and Ni, Zhenhong and Martin, Jorge H. and Chen, Lin and Jansen, Gert and Krakow, Deborah and Krejčí, Pavel},
   article_location = {OXFORD},
   article_number = {6},
   doi = {http://dx.doi.org/10.1093/hmg/ddy031},
   keywords = {ciliary function; fibroblast growth factor; FGFR3},
   language = {eng},
   issn = {0964-6906},
   journal = {Human molecular genetics},
   title = {Regulation of ciliary function by fibroblast growth factor signaling identifies FGFR3-related disorders achondroplasia and thanatophoric dysplasia as ciliopathies},
   url = {https://academic.oup.com/hmg/article/27/6/1093/4816205},
   volume = {27},
   year = {2018}
}

TY  - JOUR
ID  - 1490536
AU  - Bosáková, Michaela - Vařecha, Miroslav - Hampl, Marek - Duran, Ivan - Nită, Alexandru - Buchtová, Marcela - Dosedelova, Hana - Machát, Radek - Xie, Yangli - Ni, Zhenhong - Martin, Jorge H. - Chen, Lin - Jansen, Gert - Krakow, Deborah - Krejčí, Pavel
PY  - 2018
TI  - Regulation of ciliary function by fibroblast growth factor signaling identifies FGFR3-related disorders achondroplasia and thanatophoric dysplasia as ciliopathies
JF  - Human molecular genetics
VL  - 27
IS  - 6
SP  - 1093-1105
EP  - 1093-1105
PB  - OXFORD UNIV PRESS
SN  - 09646906
KW  - ciliary function
KW  - fibroblast growth factor
KW  - FGFR3
UR  - https://academic.oup.com/hmg/article/27/6/1093/4816205
N2  - 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.
ER  -

BOSÁKOVÁ, Michaela, Miroslav VAŘECHA, Marek HAMPL, Ivan DURAN, Alexandru NIT$\backslash$U A, Marcela BUCHTOVÁ, Hana DOSEDELOVA, Radek MACHÁT, Yangli XIE, Zhenhong NI, Jorge H. MARTIN, Lin CHEN, Gert JANSEN, Deborah KRAKOW and Pavel KREJČÍ. Regulation of ciliary function by fibroblast growth factor signaling identifies FGFR3-related disorders achondroplasia and thanatophoric dysplasia as ciliopathies. \textit{Human molecular genetics}. OXFORD: OXFORD UNIV PRESS, 2018, vol.~27, No~6, p.~1093-1105. ISSN~0964-6906. Available from: https://dx.doi.org/10.1093/hmg/ddy031.

Detailed Information on Publication Record