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

Abstract

Egr2 is a transcription factor required for peripheral nerve myelination in rodents, and mutations in Egr2 are associated with congenital hypomyelinating neuropathy (CHN) in humans. To further study its role in myelination, we generated mice harboring a hypomorphic Egr2 allele (Egr2 Lo ) that survive for up to 3 weeks postnatally, a period of active myelination in rodents. These Egr2 Lo/Lo mice provided the opportunity to study the molecular effects of Egr2 deficiency on Schwann cell biology, an analysis that was not possible previously, because of the perinatal lethality of

The Early Growth Response Gene Egr2 (Alias Krox20) Is a Novel Transcriptional Target of Transforming Growth Factor-β that Is Up-Regulated in Systemic Sclerosis and Mediates Profibrotic Responses

“…12,44 The functional distinction between Egr-1 and Egr-2 is highlighted by genetic targeting studies demonstrating that, although Egr-1-null mice show little spontaneous phenotype, 10 loss of Egr-2 is associated with embryonic lethality. 11 Moreover, biological responses can even be antagonistically regulated by Egr-1 and Egr-2. For instance, although Egr-1 enhances T-cell function, 45 Egr-2 acts as a negative regulator.…”

“…The functional divergence is highlighted by genetic studies that showed that, although Egr-1-null mice have no spontaneous phenotype, 10 targeting Egr-2 resulted in early mouse lethality due to defective myelination. 11 Functional divergence is also evident in immune regulation: Egr-2 appears to be required for immune tolerance, whereas Egr-1 enhances T-cell activity in response to T-cell receptor engagement. 12,13 These and similar observations underline the significant differences that exist between these two structurally related members of the Egr transcription factor family.…”

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

“…Enforced Sox-2 expression inhibits activation of myelin genes by Krox-20 or cAMP elevation, and inhibits myelination in co-cultures. It is upregulated following injury and co-expressed with c-Jun in the nuclei of dedifferentiating cells (Le et al, 2005;Parkinson et al, 2008).…”

“…It is elevated as myelination starts around birth and downregulated again as myelination progresses (Stewart et al, 1997b;Thatikunta et al, 1999). Furthermore, microarray analysis indicates that Id2 levels are increased after injury (Le et al, 2005). In cultured Schwann cells, Id2 is upregulated by activation of cAMP pathways, in tandem with myelin-related genes.…”

Wnt/Rspondin/β-catenin signals control axonal sorting and lineage progression in Schwann cell development

“…Axonal Notch signals promote the formation of immature SCs from precursors (7). Progression of the SC lineage beyond the immature SC stage and radial sorting are controlled by signals from both axons and the extracellular matrix, e.g., laminin/integrin β1 and the small GTPase Rac1, and by transcription regulators, e.g., Sox10 and Sox2 (8)(9)(10)(11).…”