Deciphering peripheral nerve myelination by using Schwann cell expression profiling

Abstract

Although mutations in multiple genes are associated with inherited demyelinating neuropathies, the molecular components and pathways crucial for myelination remain largely unknown. To approach this question, we performed genome-wide expression analysis in several paradigms where the status of peripheral nerve myelination is dynamically changing. Anchor gene correlation analysis, a form of microarray analysis that integrates functional information, using correlation-based clustering, with a statistically rigorous test, the Westfall and Young step-down algorithm, was applied to this data set. Biological pathways active in myelination, genes encoding proteins involved in myelin synthesis, and genes whose mutation results in myelination defects were identified. Many known genes and previously uncharacterized ESTs not heretofore associated with myelination were also identified. One of these ESTs, MASR (myelin-associated SUR4 protein), encodes a member of the SUR4 family of fatty acid desaturases, enzymes involved in elongation of very long chain fatty acids. Its specific localization in myelinating Schwann cells indicates a crucial role for MASR in normal myelin lipid synthesis.

Analysis of congenital hypomyelinating Egr2 Lo/Lo nerves identifies Sox2 as an inhibitor of Schwann cell differentiation and myelination

“…Classification of the DEC ALL gene subset by gene ontology by using DCHIP software (Table 3, which is published as supporting information on the PNAS web site) revealed an enrichment for proteins involved in lipid metabolism (e.g., high-mobility groupCoA reductase and CGT), which is consistent with the high lipid content in myelin and the coregulation of lipid biosynthesis with myelin protein expression (10,11). Additionally, myelin sheath structural proteins, such as Claudin 5 and Mupp1 (16), which interact with each other in the Schmidt-Lanterman incisures, were present in the DEC ALL data set.…”

“…Each sample contained nerves from 10 animals. RNA extraction, probe generation, and chip hybridization to MU74A V2 microarrays were described (10), and chips were scaled to 1,500 (MAS 5.0, Affymetrix).…”

“…The developmental data, including E17, P0, P2, P4, P10, and P56 nerves, was made available by Verheijen et al (11). The sciatic nerve crush data were generated as described (10), and included samples harvested at 0, 4, 7, and 14 days after injury. When these data sets were analyzed (see Methods), we found that 123 genes in the DEC set and 121 genes in the INC set were also significantly altered in the nerve development and injury data sets.…”

Negative regulation of myelination: Relevance for development, injury, and demyelinating disease

“…In the case of myelinating cells this involves downregulation of a large number of genes related to myelination (reviewed in Jessen and Mirsky, 2005;Mirsky et al, 2008;Scherer and Salzer, 2001). This includes enzymes that provide for cholesterol synthesis, structural proteins such as P 0 , myelin basic protein (MBP), and membrane associated proteins such as myelin associated glycoprotein (MAG) and periaxin (Buchstaller et al, 2004;D'Antonio et al, 2006;Leblanc et al, 2005;Nagarajan et al, 2001Nagarajan et al, , 2002Verheijen et al, 2003). This switch-off is accompanied by the activation of another group of molecules, most of which are normally found on immature cells prior to myelination.…”

Neuregulin‐1, a key axonal signal that drives Schwann cell growth and differentiation

“…Myelination requires the activation and high-level expression of myelin-specific genes, and the production of vast quantities of myelin membrane (Nagarajan et al, 2002;Verheijen et al, 2003). The process of myelination results in a huge increase in the size of a Schwann cell, particular of its membrane surface area, which was estimated to increase within a few days up to several thousand fold.…”