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Activation of sonic hedgehog signaling by a Smoothened agonist restores congenital defects in mouse models of endocrine-cerebro-osteodysplasia syndrome
- Source :
- EBioMedicine, Vol 49, Iss, Pp 305-317 (2019), EBioMedicine
- Publication Year :
- 2019
- Publisher :
- Elsevier, 2019.
-
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. Keywords: Cleft palate, Ciliopathy, Sonic hedgehog, Endocrine-cerebro-osteodysplasia (ECO) syndrome, Smoothened agonist (SAG)
- Subjects :
- 0301 basic medicine
Research paper
lcsh:Medicine
Protein Serine-Threonine Kinases
Endocrine System Diseases
Models, Biological
Ciliopathies
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
0302 clinical medicine
Central Nervous System Diseases
medicine
Animals
Hedgehog Proteins
Cilia
Sonic hedgehog
Cell Proliferation
Mice, Knockout
Smoothened agonist (SAG)
lcsh:R5-920
biology
Palate
business.industry
Cilium
lcsh:R
Genetic disorder
Gene Expression Regulation, Developmental
General Medicine
Embryo, Mammalian
medicine.disease
Smoothened Receptor
Hedgehog signaling pathway
Cell biology
Cleft Palate
Endocrine-cerebro-osteodysplasia (ECO) syndrome
Endocrine-cerebro-osteodysplasia syndrome
Disease Models, Animal
030104 developmental biology
030220 oncology & carcinogenesis
Mutation
biology.protein
Ciliopathy, Sonic hedgehog
business
Smoothened
lcsh:Medicine (General)
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 23523964
- Volume :
- 49
- Database :
- OpenAIRE
- Journal :
- EBioMedicine
- Accession number :
- edsair.doi.dedup.....66d267859276abeb77df3494693b1253