Differential regulation of NAB corepressor genes in Schwann cells.
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 null 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.


CONCLUSIONS
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.
Srinivasan
Rajini
R
Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA. rsrinivasan@wisc.edu
Jang
Sung-Wook
SW
Ward
Rebecca M
RM
Sachdev
Shrikesh
S
Ezashi
Toshihiko
T
Svaren
John
J
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D002460:Cell Line; D051638:Ether-A-Go-Go Potassium Channels / Q000502:physiology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout / Q000502:physiology; D009363:Neoplasm Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D020880:Neuregulins / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D050787:Proto-Oncogene Protein c-ets-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D012583:Schwann Cells / Q000502:physiology*; D012584:Sciatic Nerve / Q000502:physiology; D012689:Sequence Homology, Nucleic Acid
D000906:Antibodies; D051638:Ether-A-Go-Go Potassium Channels; C494071:Ets2 protein, rat; C109500:Kcnh6 protein, rat; C490623:Nab1 protein, rat; C490999:Nab2 protein, rat; D009363:Neoplasm Proteins; D020880:Neuregulins; D050787:Proto-Oncogene Protein c-ets-2; D012097:Repressor Proteins