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Activation of WNT signaling restores the facial deficits in a zebrafish with defects in cholesterol metabolism
genesis ( IF 1.5 ) Pub Date : 2020-11-16 , DOI: 10.1002/dvg.23397
Victoria L Castro 1 , Nayeli G Reyes-Nava 1 , Brianna B Sanchez 1 , Cesar G Gonzalez 1 , David Paz 1 , Anita M Quintana 1
Affiliation  

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.

中文翻译:

WNT信号的激活恢复了胆固醇代谢缺陷斑马鱼的面部缺陷

胆固醇代谢的先天性错误是胆固醇合成途径 (CSP) 突变的结果。尽管 CSP 中的突变会导致多种先天性异常综合征,但颅面异常是与这些疾病相关的标志性表型。先前的研究已经确定斑马鱼hmgcs1 的突变基因(Vu57 等位基因)编码 CSP 中的第一种酶,导致颅面发育缺陷和神经嵴细胞 (NCC) 分化异常。然而,CSP 产物破坏 NCC 分化的分子机制尚不完全清楚。已知胆固醇可调节 WNT 信号的活性,WNT 信号是 NCC 分化的既定调节器。我们假设胆固醇合成的缺陷与 WNT 信号传导减少有关,从而导致颅面发育异常。为了验证我们的假设,我们进行了药物抑制、基因表达分析和靶向救援实验的组合,以了解 CSP 和 WNT 信号在颅面发育过程中的功能。axin2表达,一种已知的 WNT 靶基因,在用 Ro-48-8071(胆固醇合成抑制剂)处理的幼虫中。此外,通过用 WNT 激动剂 I 治疗激活 WNT 信号传导完全恢复了携带 Vu57 等位基因的动物亚群中存在的颅面缺陷。总的来说,这些数据表明在颅面发育过程中 CSP 和 WNT 信号之间存在相互作用。
更新日期:2020-12-20
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