RNA-seq analysis of Schwann cell knockout of ATP citrate lyase (ACLY)

Formation of myelin by Schwann cells is tightly coupled to nervous system development and is important for neuronal function and long-term maintenance. Perturbation of myelin causes a number of specific disorders that are among the most prevalent diseases affecting the nervous system. Schwann cells synthesize myelin lipids de novo rather than relying on uptake of circulating lipids, and the metabolic sources of myelin formation and maintenance in vivo remain unresolved. One of these questions is how a central metabolite in myelin formation, Acetyl CoA, is generated in myelinating cells. Acetyl CoA-generating pathways are induced at the level of gene expression to support high demands for lipid synthesis and acetylation reactions. However, recent studies have shown that glucose-derived Acetyl CoA itself is not required for myelination, and the requirements of mitochondrially-derived Acetyl CoA has never been tested for myelination in vivo. Several older labeling studies have demonstrated the possibility that cytosolic Acetyl CoA-generating pathways from acetate/ketone bodies satisfy the high demands for lipid synthesis and histone acetylation, and we have employed knockout mice to test the required pathways. Intriguingly, metabolic pathways play different role during the postnatal synthesis of myelin lipids in the postnatal period compared to myelin maintenance postweaning. RNA-seq analysis of sciatic nerve of control and Acly knockout in Schwann cells雪旺细胞（Schwann cells）形成髓鞘的过程与神经系统发育紧密耦联，对神经元功能及长期维持至关重要。髓鞘的异常扰动会引发多种特异性疾病，这类疾病亦是影响神经系统的高发疾病之一。雪旺细胞可从头合成髓鞘脂质，而非依赖循环脂质的摄取，然而体内髓鞘形成与维持的代谢来源仍未明确。其中一个核心问题是：髓鞘形成过程中的关键代谢物乙酰辅酶A（Acetyl CoA）是如何在髓鞘形成细胞中产生的。为满足脂质合成与乙酰化反应的高需求，乙酰辅酶A生成通路会在基因表达层面被诱导激活。然而，近期研究表明，葡萄糖衍生的乙酰辅酶A本身并非髓鞘形成所必需，且线粒体衍生的乙酰辅酶A在体内髓鞘形成中的必要性从未被验证。过往多项标记实验提示，源自乙酸/酮体的胞质乙酰辅酶A生成通路可满足脂质合成与组蛋白乙酰化的高需求，本研究采用基因敲除小鼠对相关必需通路进行了验证。值得注意的是，与断奶后的髓鞘维持阶段相比，代谢通路在出生后髓鞘脂质合成阶段所发挥的作用存在显著差异。对对照组及雪旺细胞Acly基因敲除（Acly）小鼠的坐骨神经进行的RNA测序（RNA-seq）分析