Loss of Sprouty Produces a Ciliopathic Skeletal Phenotype in Mice Through Upregulation of Hedgehog Signaling

0548779 - ÚŽFG 2022 RIV US eng J - Journal Article
Hrubá, Eva - Kavková, M. - Dalecká, L. - Macholán, Miloš - Zikmund, T. - Vařecha, M. - Bosáková, Michaela - Kaiser, J. - Krejčí, Pavel - Hovoráková, M. - Buchtová, Marcela
Loss of Sprouty Produces a Ciliopathic Skeletal Phenotype in Mice Through Upregulation of Hedgehog Signaling.
Journal of Bone and Mineral Research. Roč. 36, č. 11 (2021), s. 2258-2274. ISSN 0884-0431. E-ISSN 1523-4681
R&D Projects: GA MŠMT EF15_003/0000460; GA MŠMT(CZ) LQ1601; GA ČR(CZ) GA21-04178S; GA MŠMT(CZ) LM2015062
Institutional support: RVO:67985904
Keywords : bone * analysis/ quantitation of bone * genetic animal models
OECD category: Developmental biology
Impact factor: 6.390, year: 2021
Method of publishing: Limited access
https://asep.lib.cas.cz/arl-cav/cs/csg/?repo=crepo1&key=59879401931

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.
Permanent Link: http://hdl.handle.net/11104/0324831