Regulation of cholesterol/lipid biosynthetic genes by Egr2/Krox20 during peripheral nerve myelination

Abstract

Myelination of peripheral nerves by Schwann cells requires a large amount of lipid and cholesterol biosynthesis. To understand the transcriptional coordination of the myelination process, we have investigated the developmental relationship between early growth response 2 (Egr2)/Krox20 -a pivotal regulator of peripheral nerve myelination -and the sterol regulatory element binding protein (SREBP) pathway, which controls expression of cholesterol/lipid biosynthetic genes. During myelination of sciatic nerve, there is a very significant induction of SREBP1 and SREBP2, as well as their target genes, suggesting that the SREBP transactivators are important regulators in the myelination process. Egr2/Krox20 does not appear to directly regulate the levels of SREBP pathway components, but rather, we found that Egr2/Krox20 and SREBP transactivators can synergistically activate promoters of several SREBP target genes, indicating that direct induction of cholesterol/lipid biosynthetic genes by Egr2/ Krox20 is a part of the myelination program regulated by this transactivator.

Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples

“…49 To our knowledge, there is no specific studies so far about the impact of the SREBP pathway in myelination in the central nervous system, but several studies have demonstrated the importance of this pathway in the peripheral myelination of axons. 50,51 The present implication of SREBF1 and SREBF2 as genetic susceptibility factors in schizophrenia further underscores the importance of lipid biosynthesis and myelination in the pathophysiology of schizophrenia.…”

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

“…In all of this, Pax-3 resembles c-Jun and Sox-2. Paradoxically, however, in early postnatal nerves of Krox-20 null or heterozygous mice, Pax-3 mRNA levels are lower than in control nerves (Leblanc et al, 2005). In adult nerves, Pax-3 is also upregulated after nerve transection, but it is not known whether it is involved in the control of dedifferentiation.…”

“…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.…”

Early Growth Response 1 (Egr1) Regulates Cholesterol Biosynthetic Gene Expression

“…Peaks of binding were localized to the transcription start site and extended into the proximal promoter and sometimes into the first exon of the gene. Cyp51 has been previously shown to be responsive to EGR regulation (14), as has Me1 (31). In addition to these genes, Egr1 binding was identified in the promoters of the HMG-CoA synthase (Hmgcs), farnesyl diphosphate synthase (Fdps), farnesyldiphosphate farnesyltransferase 1 (Fdft1), lanosterol synthase (Lss), sterol-4␣-carboxylate 3-dehydrogenase (Nsdhl), and malic enzyme (Me1) genes (see supplemental Fig.…”

“…Accordingly, we have shown that Egr2 can act synergistically with SREBP-2 to activate transcription of the promoters of certain cholesterol biosynthetic genes (e.g. Hmgcr) (14). Additionally, in the Krox20/Egr2 null mouse, the expression of Hmgcr and Cyp51 was significantly reduced (Ͼ80%) in peripheral nerve despite little change in SREBP levels, suggesting a role for EGR factors in the regulation of cholesterol metabolism.…”