Mutation of 3-Hydroxy-3-Methylglutaryl CoA Synthase I Reveals Requirements for Isoprenoid and Cholesterol Synthesis in Oligodendrocyte Migration Arrest, Axon Wrapping, and Myelin Gene Expression

Abstract

Myelin membrane, which ensheaths axons, has an unusually high amount of cholesterol. Cholesterol influences membrane fluidity and assembles lipid-rich microdomains within membranes, and some studies have shown that cholesterol is important for myelination. How cholesterol influences the development and differentiation of oligodendrocytes, glial cells that make myelin, is not known nor is clear whether isoprenoids, which also are products of the cholesterol biosynthetic pathway, contribute to myelination. Through a forward genetic screen in zebrafish we discovered that mutation of hmgcs1, which encodes an enzyme necessary for isoprenoid and cholesterol synthesis, causes oligodendrocyte progenitor cells (OPCs) to migrate past their target axons and to fail to express myelin genes. Drawing on a combination of pharmacological inhibitor and rescue experiments, we provide evidence that isoprenoids and protein prenylation, but not cholesterol, are required in OPCs to halt their migration at target axons. On the other hand, cholesterol, but not isoprenoids, is necessary both for axon ensheathment and myelin gene expression. Our data reveal that different products of the cholesterol biosynthetic pathway have distinct roles in oligodendrocyte development and that they together help to coordinate directed migration, axon wrapping, and gene expression.

The scales and tales of myelination: using zebrafish and mouse to study myelinating glia

“…As zebrafish represent the simplest genetically tractable model organism for studying myelination, they have recently garnered much attention from both the glial and broader neuroscience communities (Zalc et al, 2008; Lyons and Talbot, 2015; Stewart et al, 2014). One of the greatest advantages of using the zebrafish model system for studying myelination (or any area of interest) is the ability to perform both forward genetic screens and small-molecule chemical screens on thousands of individuals to define genetic and pharmacological modulators of neurodevelopment (e.g., Driever et al, 1996; Podoga et al, 2006; Kazakova et al, 2006; Rihel et al, 2010; Mathews et al, 2014; Miller et al, 2015; Kokel and Peterson, 2011). This feature of the zebrafish is not only the consequence large brood size and short generation time, but also reflects the ability to quickly screen for phenotypes in vivo in the developing embryo given their optical clarity and the rapid development of the nervous system (Figures 1 & 4) (Snyder et al, 2012).…”

HMG-CoA synthase isoenzymes 1 and 2 localize to satellite glial cells in dorsal root ganglia and are differentially regulated by peripheral nerve injury

“…Inherited HMGCS2 deficiency in human causes metabolic disorder presenting with hypoketotic hypoglycemia, encephalopathy, and hepatomegaly (Aledo et al, 2006). Mutation of HMGCS1 in zebrafish leads to abnormality in oligodendrocyte development and myelin gene expression (Mathews et al, 2014). Based on microarray and proteomics data, HMGCS1 was reported to be significantly downregulated in the ipsilateral lumbar (L) 5 DRG of L5 spinal nerve ligation (L5 SNL) rats and in the spinal cords of rats with spinal cord injury or chemical-induced spinal cord axonopathy, and sciatic nerve injury (Chen et al, 2015; D’Antonio et al, 2006; Di Narzo et al, 2015; Komori et al, 2007; Tshala-Katumbay et al, 2008).…”

Simvastatin treatment reduces the cholesterol content of membrane/lipid rafts, implicating the N -methyl-D-aspartate receptor in anxiety: a literature review

“…Balanced cholesterol homeostasis is an important aspect of nervous system function (Mathews et al, 2014).…”