EGR2 and SOX10-mediated initiation of Schwann cell myelination (Homo sapiens)
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Description
Schwann cells are glial cells of the peripheral nervous system that ensheath the peripheral nerves within a compacted lipid-rich myelin structure that is required for optimal transduction of nerve signals in motor and sensory nerves. Schwann cells develop from the neural crest in a differentiation process driven by factors derived from the Schwann cell itself, from the adjacent neuron or from the extracellular matrix (reviewed in Jessen and Mirsky, 2005). Upon peripheral nerve injury, mature Schwann cells can form repair cells that allow peripheral nerve regeneration through myelin phagocytosis and remyelination of the peripheral nerve. This process in some ways recapitulates the maturation of immature Schwann cells during development (reviewed in Jessen and Mirsky, 2016). Mature, fully myelinated Schwann cells exhibit longitudinal and radial polarization. The axon-distal abaxonal membrane interacts with elements of the basal lamina through integrins and lamins and in this way resembles the basolateral domain of polarized epithelial cells. In contrast, the axon-proximal adaxonal membrane resembles the apical domain of an epithelial cell, and is enriched with adhesion molecules and receptors that mediate interaction with ligands from the axon (reviewed in Salzer, 2015).
Schwann cells express a number of Schwann-cell specific proteins, including components of the myelin sheath such as myelin basic protein (MBP) and myelin protein zero (MPZ). In addition, Schwann cells have high lipid content relative to other membranes, and are enriched in galactosphingolipids, cholesterol and saturated long chain fatty acids (reviewed in Garbay et al, 2000). This protein and lipid profile is driven by a Schwann cell myelination transcriptional program controlled by master regulators SOX10, POU3F1 and EGR2, among others (reviewed in Svaren and Meijer, 2008; Stolt and Wegner, 2016). View original pathway at Reactome.
Schwann cells express a number of Schwann-cell specific proteins, including components of the myelin sheath such as myelin basic protein (MBP) and myelin protein zero (MPZ). In addition, Schwann cells have high lipid content relative to other membranes, and are enriched in galactosphingolipids, cholesterol and saturated long chain fatty acids (reviewed in Garbay et al, 2000). This protein and lipid profile is driven by a Schwann cell myelination transcriptional program controlled by master regulators SOX10, POU3F1 and EGR2, among others (reviewed in Svaren and Meijer, 2008; Stolt and Wegner, 2016). View original pathway at Reactome.
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gene:EGR2:SREBF2
dimergene:EGR2:SREBF2
dimergene:EGR2:SREBF2
dimerAnnotated Interactions
gene:EGR2:SREBF2
dimergene:EGR2:SREBF2
dimergene:EGR2:SREBF2
dimergene:EGR2:SREBF2
dimerExpression of POU3F1 is driven in part by the Schwann Cell Enhancer (SCE), which is bound by a dimer of SOX10, a key regulator of Schwann cell development (Jagalur et al, 2011). POU3F1 expression is also regulated by the adhesion GPCR ADGRG6 (also known as GPR126). Expression of POU3F1 and EGR2 is lost in grp126 mutant, which arrest at a promyelinating stage (Monk et al, 2009; Monk et al, 2011). ADGRG6 elevates cAMP levels through G alpha s G proteins, and may control POU3F1 expression through the cAMP-PKA-CREB pathway (Morgan et al, 1991; Lee et al, 1999; Mandemakers et al, 2000; Monk et al, 2009; Monk et al, 2011; Mogha et al, 2013; reviewed in Svaren and Meijer). CREB phosphorylation may also be regulated by the NRG1-ERBB2:ERBB3 pathway (reviewedi n Newbern and Birchmeier,2010).
After induction, POU3F1, POU3F2 (also known as OCT7) and SOX10 work together in a feedforward mechanism to activate expression of EGR2, which ultimately promotes expression of genes encoding myelin components, such as myelin protein zero (MPZ) and myelin basic protein (MBP) (Ghislain and Charnay, 2006; Le Blanc et al, 2006; Le Blanc et al, 2007; Marathe et al, 2013; reviewed in Stolt and Wegner, 2016; Svaren and Meijer, 2008)
POU3F1 protein (also known as OCT6) is required in conjunction with EGR2 to ensheath axonal neurons of the peripheral nervous system with myelin (reviewed in Svaren and Meijer, 2008). The myelination program is initiated by extracellular axonal signals such as NRG, Neuregulin1, Notch ligands and neurotrophins and is transmitted to the nucleus, ultimately controling expression of myelin-related genes, including myelin protein zero (MPZ) and myelin basic protein (MBP), among others. After synthesis, OCT6 acts in conjunction with SOX10 and EGR2, a master regulator of myelination, to drive expression of these genes (reviewed in Svaren and Meijer, 2008; Stolt and Wegner, 2016).
In addition to its other roles, EGR2 is a critical regulator of myelination by Schwann cells in the peripheral nervous system (reviewed in Svaren and Meijer, 2008). Consistent with this, Schwann cells are blocked at the promyelinating stage in EGR2 knockouts in mice (Topilko et al, 1994). Expression of EGR2 during the myelination process is controlled by a myelinating Schwann cell enhancer (MSE) 35 kb downstream of the gene (Ghislain et al, 2002). The MSE is bound by SOX10, POU3F1 and POU3F2 (Ghislain and Charnay, 2006; Reiprich et al, 2010). SOX10 in turn recruits SMARCA4, HDAC1 and HDAC2 to play overlapping but non-redundant roles in activating EGR2 expression (Jacob et al, 2011; Chen et al, 2011; Weider et al, 2012).
MAG expression is regulated in part by the binding of EGR2 and SOX10 to elements in the second intron of the gene (LeBlanc et al, 2007; Jang et al, 2006; Jones et al, 2007). Consistent with this, MAG expression is abrogated in EGR2-depleted mice and stimulated by ectopic EGR2 expression (Le et al, 2005; Nagarajan et al, 2001). At the protein level, MAG stability is postively regulated by the adhesion GPCR protein GPR98 (also known as VLGR1). GPR98 signals through G proteins, PKA and PKA to limit MAG ubiquitination and subsequent degradation, although the mechanism remains to be elucidated (Shin et al, 2013; reviewed in Mehta and Piao, 2017).
Expression of PRX initiates earlier than EGR2 during peripheral nerve cell myelination, indicating an EGR2-independent mechanism early during myelination (Parkinson et al, 2003). Candidate regulators of this early expression include SOX10 and EGR1, which is expressed in embryonic Schwann cells and with EGR2 at postnatal day 1 (Topilko et al, 1997). Sustained, upregulated expression of PRX during myelination depends on the binding of EGR2 and SOX10 to a binding site within the first intron, 4.5 kb from the transcription start site (Jones et al, 2007; Srinivasan et al, 2012). Consistent with this, expression of PRX is decreased in EGR2 null mice (Nagarajan et al, 2001; Boerkoel et al, 2001).
Expression of PRX initiates earlier than EGR2 during peripheral nerve cell myelination, indicating an EGR2-independent mechanism early during myelination (Parkinson et al, 2003). Candidate regulators of this early expression include SOX10 and EGR1, which is expressed in embryonic Schwann cells and with EGR2 at postnatal day 1 (Topilko et al, 1997). Sustained, upregulated expression of PRX during myelination depends on the binding of EGR2 and SOX10 to a binding site within the first intron, 4.5 kb from the transcription start site (Jones et al, 2007; Srinivasan et al, 2012). Consistent with this, expression of PRX is decreased in EGR2 null mice (Nagarajan et al, 2001; Boerkoel et al, 2001).
PRZ and DRP2 have partially overlapping but distinct roles in myelin sheath formation. Both are required for the formation of appositions between the plasma membrane and the myelin sheath and for the formation of Cajal bodies. PRX also contributes to normal Schwann cell elongation and regulation of internode space along the axon, which is required for nerve conduction, while DRP2 is dispensable for these activities (Court et al, 2009; Sherman et al, 2012;)
gene:EGR2:SREBF2
dimergene:EGR2:SREBF2
dimer