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HRUBÁ, E. KAVKOVÁ, M. DALECKÁ, L. MACHOLÁN, M. ZIKMUND, T. VAŘECHA, M. BOSÁKOVÁ, M. KAISER, J. KREJČÍ, P. HOVOŘÁKOVÁ, M. BUCHTOVÁ, M.
Original Title
Loss of Sprouty Produces a Ciliopathic Skeletal Phenotype in Mice Through Upregulation of Hedgehog Signaling
Type
journal article in Web of Science
Language
English
Original Abstract
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. (C) 2021 American Society for Bone and Mineral Research (ASBMR).
Keywords
BONE QCT/mu CT; ANALYSIS/QUANTITATION OF BONE; GENETIC ANIMAL MODELS; MOLECULAR PATHWAYS - DEVELOPMENT; LIMB PATTERNING; BONE MODELING AND REMODELING; HEDGEHOG; CELL/TISSUE SIGNALING
Authors
HRUBÁ, E.; KAVKOVÁ, M.; DALECKÁ, L.; MACHOLÁN, M.; ZIKMUND, T.; VAŘECHA, M.; BOSÁKOVÁ, M.; KAISER, J.; KREJČÍ, P.; HOVOŘÁKOVÁ, M.; BUCHTOVÁ, M.
Released
25. 8. 2021
Publisher
WILEY
Location
HOBOKEN
ISBN
0884-0431
Periodical
JOURNAL OF BONE AND MINERAL RESEARCH
Year of study
15
Number
124
State
United States of America
Pages from
1
Pages to
17
Pages count
URL
https://asbmr.onlinelibrary.wiley.com/doi/10.1002/jbmr.4427
BibTex
@article{BUT172867, author="Eva {Hrubá} and Michaela {Kavková} and Linda {Dalecká} and Miloš {Macholán} and Tomáš {Zikmund} and Miroslav {Vařecha} and Michaela {Bosáková} and Jozef {Kaiser} and Pavel {Krejčí} and Mária {Hovořáková} and Marcela {Buchtová}", title="Loss of Sprouty Produces a Ciliopathic Skeletal Phenotype in Mice Through Upregulation of Hedgehog Signaling", journal="JOURNAL OF BONE AND MINERAL RESEARCH", year="2021", volume="15", number="124", pages="1--17", doi="10.1002/jbmr.4427", issn="0884-0431", url="https://asbmr.onlinelibrary.wiley.com/doi/10.1002/jbmr.4427" }