Prenatal alcohol exposure disrupts Sonic hedgehog pathway and primary cilia genes in the mouse neural tube.
Prenatal alcohol exposure disrupts Sonic hedgehog pathway and primary cilia genes in the mouse neural tube.
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DOI：
10.1016/j.reprotox.2021.09.002
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Parnell SE
中科院分区：
文献类型：
--
作者：
Boschen KE;Fish EW;Parnell SE
神经形成阶段酒精暴露（NAE;胚胎日[E] 8-10）与中线颅面和CNS缺陷相关，这些缺陷可能是由于形态发生途径的破坏，如Sonic hedgehog（Shh）。值得注意的是，中线异常也是遗传性纤毛病如Joubert综合征的标志。我们测试了NAE是否改变Shh途径信号传导以及初级纤毛（对Shh途径转导至关重要的细胞器）的数量和功能。雌性C57 BL/6 J小鼠在E9时给予两个剂量的酒精（2.9 g/kg/剂量）或溶媒。收集胚胎6，12，或24小时后，和Shh，细胞周期基因，和初级纤毛的变化进行了测量，在rostroventral神经管（RVNT）。在NAE后的前24小时内，观察到Shh通路和细胞周期基因表达的减少以及全长激活剂状态下Gli 3形式的比例。RVNT体积和细胞层宽度在12小时减少。此外，在NAE后6小时观察到多个纤毛相关基因的表达改变。作为纤毛基因-乙醇相互作用的进一步测试，与溶剂处理的小鼠相比，Kif 3a杂合性小鼠在NAE后的青春期表现出扰乱行为，并且Kif 3a杂合性加剧了NAE对探索活动的过度活跃效应。这些数据表明，NAE下调神经管区域中的Shh通路，该区域产生酒精敏感性脑结构，并将初级纤毛功能的破坏或“短暂性纤毛病”鉴定为产前酒精发病的可能细胞机制。
Neurulation-stage alcohol exposure (NAE; embryonic day [E] 8–10) is associated with midline craniofacial and CNS defects that likely arise from disruption of morphogen pathways, such as Sonic hedgehog (Shh). Notably, midline anomalies are also a hallmark of genetic ciliopathies such as Joubert syndrome. We tested whether NAE alters Shh pathway signaling and the number and function of primary cilia, organelles critical for Shh pathway transduction. Female C57BL/6J mice were administered two doses of alcohol (2.9 g/kg/dose) or vehicle on E9. Embryos were collected 6, 12, or 24 hr later, and changes to Shh, cell cycle genes, and primary cilia were measured in the rostroventral neural tube (RVNT). Within the first 24 hours post-NAE, reductions in Shh pathway and cell cycle gene expression and the ratio of Gli3 forms in the full-length activator state were observed. RVNT volume and cell layer width were reduced at 12 hr. In addition, altered expression of multiple cilia-related genes was observed at 6 hr post-NAE. As a further test of cilia gene-ethanol interaction, mice heterozygous for Kif3a exhibited perturbed behavior during adolescence following NAE compared to vehicle-treated mice, and Kif3a heterozygosity exacerbated the hyperactive effects of NAE on exploratory activity. These data demonstrate that NAE downregulates the Shh pathway in a region of the neural tube that gives rise to alcohol-sensitive brain structures and identifies disruption of primary cilia function, or a “transient ciliopathy”, as a possible cellular mechanism of prenatal alcohol pathogenesis.
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