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. Overall design: RNA-seq analysis of sciatic nerve of control and Acly knockout in Schwann cells