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

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

doi:10.1016/j.ebiom.2019.10.016

Cited by 14 publications

(18 citation statements)

References 36 publications

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“…Despite these advances, a molecular mechanism by which facial abnormalities develop in animals with reduced cholesterol synthesis has not been characterized. Multiple studies have suggested that defects in cholesterol synthesis are related to altered SHH signaling (Shin et al, 2019), however homozygous Vu57 mutants do not show altered SHH signaling during early CNCC development (Quintana et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

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Activation of WNT signaling restores the facial deficits in a zebrafish with defects in cholesterol metabolism

Castro

Reyes-Nava

Sanchez

et al. 2020

Genesis

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Inborn errors of cholesterol metabolism occur as a result of mutations in the cholesterol synthesis pathway (CSP). Although mutations in the CSP cause a multiple congenital anomaly syndrome, craniofacial abnormalities are a hallmark phenotype associated with these disorders. Previous studies have established that mutation of the zebrafish hmgcs1 gene (Vu57 allele), which encodes the first enzyme in the CSP, causes defects in craniofacial development and abnormal neural crest cell (NCC) differentiation. However, the molecular mechanisms by which the products of the CSP disrupt NCC differentiation are not completely known. Cholesterol is known to regulate the activity of WNT signaling, an established regulator of NCC differentiation. We hypothesized that defects in cholesterol synthesis are associated with reduced WNT signaling, consequently resulting in abnormal craniofacial development. To test our hypothesis we performed a combination of pharmaceutical inhibition, gene expression assays, and targeted rescue experiments to understand the function of the CSP and WNT signaling during craniofacial development. We demonstrate reduced expression of four canonical WNT downstream target genes in homozygous carriers of the Vu57 allele and reduced axin2 expression, a known WNT target gene, in larvae treated with Ro-48-8071, an inhibitor of cholesterol synthesis. Moreover, activation of WNT signaling via treatment with WNT agonist I completely restored the craniofacial defects present in a subset of animals carrying the Vu57 allele. Collectively, these data suggest interplay between the CSP and WNT signaling during craniofacial development.

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Section: Discussionmentioning

confidence: 99%

“…Cholesterol is required for the activation of various cell signaling cascades (Shimomura et al, 2019), including SHH and WNT, both of which are required for craniofacial development (Shimomura et al, 2019; Shin et al, 2019). For example, WNT activation requires the activity of dishevelled, a scaffolding protein (Bernatik et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Activation of WNT signaling restores the facial deficits in a zebrafish with defects in cholesterol metabolism

Castro

Reyes-Nava

Sanchez

et al. 2020

Genesis

View full text Add to dashboard Cite

show abstract

“…Despite these advances, a molecular mechanism by which facial abnormalities develop in these animals has not been characterized. Multiple studies have suggested that defects in cholesterol synthesis are related to defects in SHH signaling (Shin et al, 2019), however homozygous mutation of the Vu57 allele does not affect SHH signaling (Quintana et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Cholesterol is required for the activation of various cell signaling cascades (Shimomura et al, 2019), including SHH and WNT, both of which are required for craniofacial development (Shimomura et al, 2019; Shin et al, 2019). For example, WNT activation requires the activity of disheveled, a scaffolding protein (Bernatik et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Activation of WNT signaling restores the facial deficits in a zebrafish with defects in cholesterol metabolism

Castro

Reyes-Nava

Sanchez

et al. 2020

Preprint

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BackgroundInborn errors of cholesterol metabolism occur as a result of mutations in the cholesterol synthesis pathway (CSP). Although mutations in the CSP cause a multiple congenital anomaly syndrome, craniofacial abnormalities are a hallmark phenotype associated with these disorders. Previous studies have established that mutation of the zebrafish hmgcs1 gene (Vu57 allele), which encodes the first enzyme in the CSP, causes defects in craniofacial development and abnormal neural crest cell (NCC) differentiation. However, the molecular mechanisms by which the products of the CSP disrupt NCC differentiation are not completely known. Cholesterol is known to regulate the activity of WNT signaling, an established regulator of NCC differentiation. We hypothesized that defects in cholesterol synthesis reduce WNT signaling, consequently resulting in abnormal craniofacial development.MethodsTo test our hypothesis we performed a combination of pharmaceutical inhibition, gene expression assays, and targeted rescue experiments to understand the function of CSP and WNT signaling during craniofacial development.ResultsWe demonstrate reduced expression of axin2, a WNT downstream target gene in homozygous carriers of the Vu57 allele and in larvae treated with Ro-48-8071, which inhibits the synthesis of cholesterol. Moreover, activation of WNT signaling via treatment with a WNT agonist completely restored the craniofacial defects present in the Vu57 allele.ConclusionsCollectively, these data suggest interplay between the CSP and WNT signaling during craniofacial development.

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“…The intestinal cell kinase ( ICK ) gene encoding for a mitogen-activated protein (MAP) kinase involved in activating Shh signaling during development is downregulated during endocrine-cerebro-osteodysplasia (ECO), a syndrome that includes CP. As the first study to attempt prenatal pharmaceutical activation of Shh signaling, Shin et al (2019) injected a small-molecule agonist for Smoothened (SAG) intraperitoneally into pregnant Ick tm1a/+ mice at various stages. Although success in palatal closures showed variable efficacy, the highest efficiency was achieved at E11.25, indicating that developmental windows are critical for restoring molecular homeostasis in Shh-mediated actions.…”

Section: Prenatal Approachesmentioning

confidence: 99%

Molecular Diagnostics and In Utero Therapeutics for Orofacial Clefts

et al. 2020

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Orofacial clefts and their management impose a substantial burden on patients, on their families, and on the health system. Under the current standard of care, affected patients are subjected to a lifelong journey of corrective surgeries and multidisciplinary management to replace bone and soft tissues, as well as restore esthetics and physiologic functions while restoring self-esteem and psychological health. Hence, a better understanding of the dynamic interplay of molecular signaling pathways at critical phases of palate development is necessary to pioneer novel prenatal interventions. Such pathways include transforming growth factor–β ( Tgfβ), sonic hedgehog ( Shh), wingless-integrated site ( Wnt)/β-catenin, bone morphogenetic protein ( Bmp), and fibroblast growth factor ( Fgf) and its associated receptors, among others. Here, we summarize commonly used surgical methods used to correct cleft defects postnatally. We also review the advances made in prenatal diagnostics of clefts through imaging and genomics and the various in utero surgical corrections that have been attempted thus far. An overview of how key mediators of signaling that drive palatogenesis are emphasized in the context of the framework and rationale for the development and testing of therapeutics in animal model systems and in humans is provided. The pros and cons of in utero therapies that can potentially restore molecular homeostasis needed for the proper growth and fusion of palatal shelves are presented. The theme advanced throughout this review is the need to develop preclinical molecular therapies that could ultimately be translated into human trials that can correct orofacial clefts at earlier stages of development.

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

Cited by 14 publications

References 36 publications

Activation of WNT signaling restores the facial deficits in a zebrafish with defects in cholesterol metabolism

Activation of WNT signaling restores the facial deficits in a zebrafish with defects in cholesterol metabolism

Activation of WNT signaling restores the facial deficits in a zebrafish with defects in cholesterol metabolism

Molecular Diagnostics and In Utero Therapeutics for Orofacial Clefts

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