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Differential regulation of NAB corepressor genes in Schwann cells.

Srinivasan R, Jang SW, Ward RM, Sachdev S, Ezashi T, Svaren J - BMC Mol. Biol. (2007)

Bottom Line: Although Egr2 expression activates the Nab2 promoter more highly than Nab1, we surprisingly found that only Nab1 - but not Nab2 - expression levels were reduced in sciatic nerve from Egr2 mice.Although Nab1 and Nab2 play partially redundant roles, regulation of Nab2 expression by ETS factors explains several observations regarding regulation of NAB genes.Finally, these data suggest that NAB proteins are not only feedback inhibitors of Egr2, but rather that co-induction of Egr2 and NAB genes is involved in forming an Egr2/NAB complex that is crucial for regulation of gene expression.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA. rsrinivasan@wisc.edu

ABSTRACT

Background: Myelination of peripheral nerves by Schwann cells requires not only the Egr2/Krox-20 transactivator, but also the NGFI-A/Egr-binding (NAB) corepressors, which modulate activity of Egr2. Previous work has shown that axon-dependent expression of Egr2 is mediated by neuregulin stimulation, and NAB corepressors are co-regulated with Egr2 expression in peripheral nerve development. NAB corepressors have also been implicated in macrophage development, cardiac hypertrophy, prostate carcinogenesis, and feedback regulation involved in hindbrain development.

Results: To test the mechanism of NAB regulation in Schwann cells, transfection assays revealed that both Nab1 and Nab2 promoters are activated by Egr2 expression. Furthermore, direct binding of Egr2 at these promoters was demonstrated in vivo by chromatin immunoprecipitation analysis of myelinating sciatic nerve, and binding of Egr2 to the Nab2 promoter was stimulated by neuregulin in primary Schwann cells. Although Egr2 expression activates the Nab2 promoter more highly than Nab1, we surprisingly found that only Nab1 - but not Nab2 - expression levels were reduced in sciatic nerve from Egr2 mice. Analysis of the Nab2 promoter showed that it is also activated by ETS proteins (Ets2 and Etv1/ER81) and is bound by Ets2 in vivo.

Conclusion: Overall, these results indicate that induction of Nab2 expression in Schwann cells involves not only Egr2, but also ETS proteins that are activated by neuregulin stimulation. Although Nab1 and Nab2 play partially redundant roles, regulation of Nab2 expression by ETS factors explains several observations regarding regulation of NAB genes. Finally, these data suggest that NAB proteins are not only feedback inhibitors of Egr2, but rather that co-induction of Egr2 and NAB genes is involved in forming an Egr2/NAB complex that is crucial for regulation of gene expression.

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Model for regulation of NAB expression. The figure indicates a model for regulation of NAB proteins during myelination, based on the requirement of NAB proteins for peripheral nerve myelination. In the first model (A), neuregulin/erbB signaling (and/or other axon-dependent signals) trigger expression of Egr2/Krox20 in myelinating Schwann cells, and the induction of NAB proteins by binding of Egr2/Krox20 acts as a negative feedback control to limit activation of specific target genes that are important for myelination. B) The second model suggests that co-induction of Egr2 and NAB proteins is mediated by neuregulin-activated expression of ETS factors. Activation of ETS factors induces sufficient amounts of NAB proteins so that an Egr2/NAB complex can actively repress specific target genes. It is noted that these two models are not necessarily mutually exclusive and could apply to different target genes in different tissues.
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Figure 8: Model for regulation of NAB expression. The figure indicates a model for regulation of NAB proteins during myelination, based on the requirement of NAB proteins for peripheral nerve myelination. In the first model (A), neuregulin/erbB signaling (and/or other axon-dependent signals) trigger expression of Egr2/Krox20 in myelinating Schwann cells, and the induction of NAB proteins by binding of Egr2/Krox20 acts as a negative feedback control to limit activation of specific target genes that are important for myelination. B) The second model suggests that co-induction of Egr2 and NAB proteins is mediated by neuregulin-activated expression of ETS factors. Activation of ETS factors induces sufficient amounts of NAB proteins so that an Egr2/NAB complex can actively repress specific target genes. It is noted that these two models are not necessarily mutually exclusive and could apply to different target genes in different tissues.

Mentions: Several groups have proposed that the induction of Nab2 constitutes a negative feedback loop in which EGR activators induce expression of their own corepressor [2,26,39,53]. Our studies refine this model by showing that other neuregulin-regulated pathways direct Nab2 expression. In addition, recent publications have shown that Egr2 is required for certain gene repression mechanisms during myelination [11,12]. Therefore, we suggest that the induction of NAB proteins does not merely constitute a negative feedback loop, but rather, that co-induction of Egr2 and NAB proteins by axon-dependent signals (e.g. neuregulin/erbB) is required to form an Egr2/NAB complex that actively represses transcription of specific genes during peripheral nerve myelination (Figure 8). These results are consistent with our demonstration of direct repression of the Rad gene by an Egr2/NAB complex in Schwann cells [6,22], as well as recent publications implicating repression by the Egr2/NAB complex in macrophages and cardiomyocytes [23,63].


Differential regulation of NAB corepressor genes in Schwann cells.

Srinivasan R, Jang SW, Ward RM, Sachdev S, Ezashi T, Svaren J - BMC Mol. Biol. (2007)

Model for regulation of NAB expression. The figure indicates a model for regulation of NAB proteins during myelination, based on the requirement of NAB proteins for peripheral nerve myelination. In the first model (A), neuregulin/erbB signaling (and/or other axon-dependent signals) trigger expression of Egr2/Krox20 in myelinating Schwann cells, and the induction of NAB proteins by binding of Egr2/Krox20 acts as a negative feedback control to limit activation of specific target genes that are important for myelination. B) The second model suggests that co-induction of Egr2 and NAB proteins is mediated by neuregulin-activated expression of ETS factors. Activation of ETS factors induces sufficient amounts of NAB proteins so that an Egr2/NAB complex can actively repress specific target genes. It is noted that these two models are not necessarily mutually exclusive and could apply to different target genes in different tissues.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2235890&req=5

Figure 8: Model for regulation of NAB expression. The figure indicates a model for regulation of NAB proteins during myelination, based on the requirement of NAB proteins for peripheral nerve myelination. In the first model (A), neuregulin/erbB signaling (and/or other axon-dependent signals) trigger expression of Egr2/Krox20 in myelinating Schwann cells, and the induction of NAB proteins by binding of Egr2/Krox20 acts as a negative feedback control to limit activation of specific target genes that are important for myelination. B) The second model suggests that co-induction of Egr2 and NAB proteins is mediated by neuregulin-activated expression of ETS factors. Activation of ETS factors induces sufficient amounts of NAB proteins so that an Egr2/NAB complex can actively repress specific target genes. It is noted that these two models are not necessarily mutually exclusive and could apply to different target genes in different tissues.
Mentions: Several groups have proposed that the induction of Nab2 constitutes a negative feedback loop in which EGR activators induce expression of their own corepressor [2,26,39,53]. Our studies refine this model by showing that other neuregulin-regulated pathways direct Nab2 expression. In addition, recent publications have shown that Egr2 is required for certain gene repression mechanisms during myelination [11,12]. Therefore, we suggest that the induction of NAB proteins does not merely constitute a negative feedback loop, but rather, that co-induction of Egr2 and NAB proteins by axon-dependent signals (e.g. neuregulin/erbB) is required to form an Egr2/NAB complex that actively represses transcription of specific genes during peripheral nerve myelination (Figure 8). These results are consistent with our demonstration of direct repression of the Rad gene by an Egr2/NAB complex in Schwann cells [6,22], as well as recent publications implicating repression by the Egr2/NAB complex in macrophages and cardiomyocytes [23,63].

Bottom Line: Although Egr2 expression activates the Nab2 promoter more highly than Nab1, we surprisingly found that only Nab1 - but not Nab2 - expression levels were reduced in sciatic nerve from Egr2 mice.Although Nab1 and Nab2 play partially redundant roles, regulation of Nab2 expression by ETS factors explains several observations regarding regulation of NAB genes.Finally, these data suggest that NAB proteins are not only feedback inhibitors of Egr2, but rather that co-induction of Egr2 and NAB genes is involved in forming an Egr2/NAB complex that is crucial for regulation of gene expression.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA. rsrinivasan@wisc.edu

ABSTRACT

Background: Myelination of peripheral nerves by Schwann cells requires not only the Egr2/Krox-20 transactivator, but also the NGFI-A/Egr-binding (NAB) corepressors, which modulate activity of Egr2. Previous work has shown that axon-dependent expression of Egr2 is mediated by neuregulin stimulation, and NAB corepressors are co-regulated with Egr2 expression in peripheral nerve development. NAB corepressors have also been implicated in macrophage development, cardiac hypertrophy, prostate carcinogenesis, and feedback regulation involved in hindbrain development.

Results: To test the mechanism of NAB regulation in Schwann cells, transfection assays revealed that both Nab1 and Nab2 promoters are activated by Egr2 expression. Furthermore, direct binding of Egr2 at these promoters was demonstrated in vivo by chromatin immunoprecipitation analysis of myelinating sciatic nerve, and binding of Egr2 to the Nab2 promoter was stimulated by neuregulin in primary Schwann cells. Although Egr2 expression activates the Nab2 promoter more highly than Nab1, we surprisingly found that only Nab1 - but not Nab2 - expression levels were reduced in sciatic nerve from Egr2 mice. Analysis of the Nab2 promoter showed that it is also activated by ETS proteins (Ets2 and Etv1/ER81) and is bound by Ets2 in vivo.

Conclusion: Overall, these results indicate that induction of Nab2 expression in Schwann cells involves not only Egr2, but also ETS proteins that are activated by neuregulin stimulation. Although Nab1 and Nab2 play partially redundant roles, regulation of Nab2 expression by ETS factors explains several observations regarding regulation of NAB genes. Finally, these data suggest that NAB proteins are not only feedback inhibitors of Egr2, but rather that co-induction of Egr2 and NAB genes is involved in forming an Egr2/NAB complex that is crucial for regulation of gene expression.

Show MeSH
Related in: MedlinePlus