1. Activation of sonic hedgehog signaling by a Smoothened agonist restores congenital defects in mouse models of endocrine-cerebro-osteodysplasia syndrome.
- Author
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Shin JO, Song J, Choi HS, Lee J, Lee K, Ko HW, and Bok J
- Subjects
- Animals, Cell Proliferation, Central Nervous System Diseases genetics, Cilia metabolism, Cleft Palate pathology, Disease Models, Animal, Embryo, Mammalian abnormalities, Embryo, Mammalian pathology, Endocrine System Diseases genetics, Gene Expression Regulation, Developmental, Mice, Knockout, Models, Biological, Mutation genetics, Palate abnormalities, Palate embryology, Palate ultrastructure, Protein Serine-Threonine Kinases deficiency, Protein Serine-Threonine Kinases metabolism, Central Nervous System Diseases congenital, Central Nervous System Diseases metabolism, Endocrine System Diseases congenital, Endocrine System Diseases metabolism, Hedgehog Proteins metabolism, Signal Transduction, Smoothened Receptor agonists
- Abstract
Background: Endocrine-cerebro-osteodysplasia (ECO) syndrome is a genetic disorder associated with congenital defects of the endocrine, cerebral, and skeletal systems in humans. ECO syndrome is caused by mutations of the intestinal cell kinase (ICK) gene, which encodes a mitogen-activated protein (MAP) kinase-related kinase that plays a critical role in controlling the length of primary cilia. Lack of ICK function disrupts transduction of sonic hedgehog (SHH) signaling, which is important for development and homeostasis in humans and mice. Craniofacial structure abnormalities, such as cleft palate, are one of the most common defects observed in ECO syndrome patients, but the role of ICK in palatal development has not been studied., Methods: Using Ick-mutant mice, we investigated the mechanisms by which ICK function loss causes cleft palate and examined pharmacological rescue of the congenital defects., Findings: SHH signaling was compromised with abnormally elongated primary cilia in the developing palate of Ick-mutant mice. Cell proliferation was significantly decreased, resulting in failure of palatal outgrowth, although palatal adhesion and fusion occurred normally. We thus attempted to rescue the congenital palatal defects of Ick mutants by pharmacological activation of SHH signaling. Treatment of Ick-mutant mice with an agonist for Smoothened (SAG) rescued several congenital defects, including cleft palate., Interpretations: The recovery of congenital defects by pharmacological intervention in the mouse models for ECO syndrome highlights prenatal SHH signaling modulation as a potential therapeutic measure to overcome congenital defects of ciliopathies., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
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