Publication detail

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

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

17

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"
}