Activation of sonic hedgehog signaling by a Smoothened agonist restores congenital defects in mouse models of endocrine-cerebro-osteodysplasia syndrome

Jeong Oh Shin, Jieun Song, Han Seul Choi, Jisu Lee, Kyeong Lee, Hyuk Wan Ko, Jinwoong Bok

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7 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)305-317
Number of pages13
Publication statusPublished - 2019 Nov

Bibliographical note

Funding Information:
This research was supported by the National Research Foundation of Korea Grant ( NRF-2014M3A9D5A01073969 and NRF-2018R1A2B2008166 to H.W.K.; NRF-2016R1A5A2008630 and NRF-2017R1A2B3009133 to J.B; NRF-2016R1A6A3A11932191 to J.S; NRF-2018R1A5A2023127 to K.L) and by the Yonsei University Future Leading Research Initiative ( 2015-22-0058 to J.B). The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

Publisher Copyright:
© 2019 The Author(s)

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)


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