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

Background: 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 stu...

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Bibliographic Details
Published inbioRxiv
Main Authors Castro, Victoria L, Reyes-Nava, Nayeli G, Sanchez, Brianna, Gonzalez, Cesar G, Quintana, Anita M
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 14.02.2020
Subjects
Alleles
Cell differentiation
Cholesterol
Craniofacial growth
Danio rerio
Defects
Embryos
Gene expression
Inborn errors of metabolism
Lipid metabolism
Metabolism
Molecular modelling
Mutation
Neural crest
Phenotypes
Wnt protein
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Summary:Background: 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 reduce WNT signaling, consequently resulting in abnormal craniofacial development. Methods: To 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. Results: We 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. Conclusions: Collectively, these data suggest interplay between the CSP and WNT signaling during craniofacial development.
DOI:10.1101/2020.02.14.949958