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Loss of Sprouty Produces a Ciliopathic Skeletal Phenotype in Mice Through Upregulation of Hedgehog Signaling
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SYSNO ASEP 0548779 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Loss of Sprouty Produces a Ciliopathic Skeletal Phenotype in Mice Through Upregulation of Hedgehog Signaling Author(s) Hrubá, Eva (UZFG-Y) ORCID
Kavková, M. (CZ)
Dalecká, L. (CZ)
Macholán, Miloš (UZFG-Y) RID, ORCID
Zikmund, T. (CZ)
Vařecha, M. (CZ)
Bosáková, Michaela (UZFG-Y) ORCID
Kaiser, J. (CZ)
Krejčí, Pavel (UZFG-Y) ORCID
Hovoráková, M. (CZ)
Buchtová, Marcela (UZFG-Y) RID, ORCIDSource Title Journal of Bone and Mineral Research. - : Wiley - ISSN 0884-0431
Roč. 36, č. 11 (2021), s. 2258-2274Number of pages 17 s. Publication form Print - P Language eng - English Country US - United States Keywords bone ; analysis/ quantitation of bone ; genetic animal models 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) LQ1601 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) GA21-04178S GA ČR - Czech Science Foundation (CSF) LM2015062 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Limited access Institutional support UZFG-Y - RVO:67985904 UT WOS 000697316300001 EID SCOPUS 85115147593 DOI 10.1002/jbmr.4427 Annotation The Sprouty family is a highly conserved group of intracellular modulators of receptor tyrosine kinase (RTK)-signaling pathways, which have been recently linked to primary cilia. Disruptions in the structure and function of primary cilia cause inherited disorders called ciliopathies. We aimed to evaluate Sprouty2 and Sprouty4 gene-dependent alterations of ciliary structure and to focus on the determination of its association with Hedgehog signaling defects in chondrocytes. Analysis of the transgenic mice phenotype with Sprouty2 and Sprouty4 deficiency revealed several defects, including improper endochondral bone formation and digit patterning, or craniofacial and dental abnormalities. Moreover, reduced bone thickness and trabecular bone mass, skull deformities, or chondromalike lesions were revealed. All these pathologies might be attributed to ciliopathies. Elongation of the ciliary axonemes in embryonic and postnatal growth plate chondrocytes was observed in Sprouty2(-/-) and Sprouty2(+/-)/Sprouty4(-/-) mutants compared with corre- sponding littermate controls. Also, cilia-dependent Hedgehog signaling was upregulated in Sprouty2/4 mutant animals. Ptch1 and Ihh expression were upregulated in the autopodium and the proximal tibia of Sprouty2(-/-)/Sprouty4(-/-) mutants. Increased levels of the GLI3 repressor (GLI3R) form were detected in Sprouty2/4 mutant primary fibroblast embryonic cell cultures and tissues. These findings demonstrate that mouse lines deficient in Sprouty proteins manifest phenotypic features resembling ciliopathic phenotypes in multiple aspects and may serve as valuable models to study the association between overactivation of RTK and dysfunction of primary cilia during skeletogenesis. Workplace Institute of Animal Physiology and Genetics Contact Jana Zásmětová, knihovna@iapg.cas.cz, Tel.: 315 639 554 Year of Publishing 2022 Electronic address https://asep.lib.cas.cz/arl-cav/cs/csg/?repo=crepo1&key=59879401931
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