Genomes and Genes
early growth response protein 2
Summary: An early growth response transcription factor that controls the formation of the MYELIN SHEATH around peripheral AXONS by SCHWANN CELLS. Mutations in EGR2 transcription factor have been associated with HEREDITARY MOTOR AND SENSORY NEUROPATHIES such as CHARCOT-MARIE-TOOTH DISEASE.
- Stedman A, Lecaudey V, Havis E, Anselme I, Wassef M, Gilardi Hebenstreit P, et al. A functional interaction between Irx and Meis patterns the anterior hindbrain and activates krox20 expression in rhombomere 3. Dev Biol. 2009;327:566-77 pubmed publisher..Together, our data point to an essential function of Iroquois transcription factors in krox20 activation and, more generally, in anterior hindbrain specification. ..
- Myouzen K, Kochi Y, Shimane K, Fujio K, Okamura T, Okada Y, et al. Regulatory polymorphisms in EGR2 are associated with susceptibility to systemic lupus erythematosus. Hum Mol Genet. 2010;19:2313-20 pubmed publisher..Therefore, EGR2 is a genetic risk factor for SLE, in which increased gene expression may contribute to SLE pathogenesis. ..
- Pospisil V, Vargova K, Kokavec J, Rybarova J, Savvulidi F, Jonasova A, et al. Epigenetic silencing of the oncogenic miR-17-92 cluster during PU.1-directed macrophage differentiation. EMBO J. 2011;30:4450-64 pubmed publisher..We propose that upon macrophage differentiation PU.1 represses the miR-17-92 cluster promoter by an Egr-2/Jarid1b-mediated H3K4 demethylation mechanism whose deregulation may contribute to leukaemic states. ..
- Nonchev S, Vesque C, Maconochie M, Seitanidou T, Ariza McNaughton L, Frain M, et al. Segmental expression of Hoxa-2 in the hindbrain is directly regulated by Krox-20. Development. 1996;122:543-54 pubmed..Therefore, the segmental phenotypes in the Krox-20 mutants are likely to reflect the role of Krox-20 in directly regulating multiple Hox genes. ..
- Levi G, Topilko P, Schneider Maunoury S, Lasagna M, Mantero S, Pesce B, et al. Role of Krox-20 in endochondral bone formation. Ann N Y Acad Sci. 1996;785:288-91 pubmed
- Warner L, Mancias P, Butler I, McDonald C, Keppen L, Koob K, et al. Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies. Nat Genet. 1998;18:382-4 pubmed
- Murphy P, Topilko P, Schneider Maunoury S, Seitanidou T, Baron van Evercooren A, Charnay P. The regulation of Krox-20 expression reveals important steps in the control of peripheral glial cell development. Development. 1996;122:2847-57 pubmed..iii) In sensory ganglia, the microenvironment is capable of negatively regulating Krox-20, presumably by preventing the conversion of satellite glial cells toward a Schwann cell-like phenotype. ..
- Harris J, Bishop K, Phillips N, Mordes J, Greiner D, Rossini A, et al. Early growth response gene-2, a zinc-finger transcription factor, is required for full induction of clonal anergy in CD4+ T cells. J Immunol. 2004;173:7331-8 pubmed..These data indicate that sustained Egr-2 expression is necessary to induce a full anergic state through the actions of genes regulated by this transcription factor. ..
- Honkaniemi J, Sharp F. Prolonged expression of zinc finger immediate-early gene mRNAs and decreased protein synthesis following kainic acid induced seizures. Eur J Neurosci. 1999;11:10-7 pubmed
- Phelps E, Sweeney K, Blader I. Toxoplasma gondii rhoptry discharge correlates with activation of the early growth response 2 host cell transcription factor. Infect Immun. 2008;76:4703-12 pubmed publisher..Collectively, these data indicate that EGR2 is specifically upregulated by a parasite-derived secreted factor that is most likely a resident rhoptry protein...
- Monk K, Naylor S, Glenn T, Mercurio S, Perlin J, Dominguez C, et al. A G protein-coupled receptor is essential for Schwann cells to initiate myelination. Science. 2009;325:1402-5 pubmed publisher..We propose that Gpr126 drives the differentiation of promyelinating Schwann cells by elevating cAMP levels, thereby triggering Oct6 expression and myelination. ..
- Lawson V, Weston K, Maurice D. Early growth response 2 regulates the survival of thymocytes during positive selection. Eur J Immunol. 2010;40:232-41 pubmed publisher..Therefore, expression of Egr2 following positive selection links the initial TCR signaling event to subsequent survival of signaled cells. ..
- Arthur Farraj P, Mirsky R, Parkinson D, Jessen K. A double point mutation in the DNA-binding region of Egr2 switches its function from inhibition to induction of proliferation: A potential contribution to the development of congenital hypomyelinating neuropathy. Neurobiol Dis. 2006;24:159-69 pubmed..Furthermore, mutant Egr2 upregulates cyclin D1 and reduces levels of the cell cycle inhibitor, p27. These observations add significant new evidence to explain how this mutation leads to congenital hypomyelinating neuropathy in humans. ..
- De S, Shuler C, Turman J. The ontogeny of Krox-20 expression in brainstem and cerebellar neurons. J Chem Neuroanat. 2003;25:213-26 pubmed
- Swanberg S, Nagarajan R, Peddada S, Yasui D, LaSalle J. Reciprocal co-regulation of EGR2 and MECP2 is disrupted in Rett syndrome and autism. Hum Mol Genet. 2009;18:525-34 pubmed publisher..In contrast to age-matched Controls, RTT and autism postmortem cortex samples showed significant reduction in EGR2. Together, these data support a role of dysregulation of an activity-dependent EGR2/MeCP2 pathway in RTT and autism. ..
- Chatonnet F, del Toro E, Voiculescu O, Charnay P, Champagnat J. Different respiratory control systems are affected in homozygous and heterozygous kreisler mutant mice. Eur J Neurosci. 2002;15:684-92 pubmed..A different rhythm-promoting system originates in r5 and kreisler controls the development of antiapneic and chemosensory signal transmission at this level. ..
- Laslo P, Spooner C, Warmflash A, Lancki D, Lee H, Sciammas R, et al. Multilineage transcriptional priming and determination of alternate hematopoietic cell fates. Cell. 2006;126:755-66 pubmed..These results are used to assemble and mathematically model a gene regulatory network that exhibits both graded and bistable behaviors and accounts for the onset and resolution of mixed lineage patterns during cell fate determination. ..
- Wiley M, Teygong C, Phelps E, Radke J, Blader I. Serum response factor regulates immediate early host gene expression in Toxoplasma gondii-infected host cells. PLoS ONE. 2011;6:e18335 pubmed publisher..Together, these data define Serum Response Factor as a host cell transcription factor that regulates immediate early gene expression in Toxoplasma-infected cells. ..
- Zhu B, Symonds A, Martin J, Kioussis D, Wraith D, Li S, et al. Early growth response gene 2 (Egr-2) controls the self-tolerance of T cells and prevents the development of lupuslike autoimmune disease. J Exp Med. 2008;205:2295-307 pubmed publisher..These results demonstrate that Egr-2 is an intrinsic regulator of effector T cells and controls the expansion of self-reactive T cells and development of autoimmune disease. ..
- Yokota I, Sasaki Y, Kashima L, Idogawa M, Tokino T. Identification and characterization of early growth response 2, a zinc-finger transcription factor, as a p53-regulated proapoptotic gene. Int J Oncol. 2010;37:1407-16 pubmed..Conversely, inactivation of EGR2 attenuated p53-mediated apoptosis. The results presented here suggest that EGR2 is a direct transcriptional target of p53 family that can in part mediate the p53-dependent apoptotic pathway. ..
- Coutinho A, Borday C, Gilthorpe J, Jungbluth S, Champagnat J, Lumsden A, et al. Induction of a parafacial rhythm generator by rhombomere 3 in the chick embryo. J Neurosci. 2004;24:9383-90 pubmed..The r4 rhythm generator appears to be homologous to a murine respiratory parafacial neuronal system developing in r4 under the control of Krox20 and Hoxa1. These results identify a late role for Krox20 at the onset of neurogenesis. ..
- Parkinson D, Bhaskaran A, Droggiti A, Dickinson S, D Antonio M, Mirsky R, et al. Krox-20 inhibits Jun-NH2-terminal kinase/c-Jun to control Schwann cell proliferation and death. J Cell Biol. 2004;164:385-94 pubmed..Krox-20 also up-regulates the scaffold protein JNK-interacting protein 1 (JIP-1). We propose this as a possible component of the mechanism by which Krox-20 regulates JNK activity during Schwann cell development. ..
- Hirano S, Anuradha C, Kanno S. krox-20/egr-2 is up-regulated following non-specific and homophilic adhesion in rat macrophages. Immunology. 2002;107:86-92 pubmed
- Reiprich S, Kriesch J, Schreiner S, Wegner M. Activation of Krox20 gene expression by Sox10 in myelinating Schwann cells. J Neurochem. 2010;112:744-54 pubmed publisher..All required regions are conserved in several closely related POU and Sox proteins thus explaining why Oct6 and Sox10 can be replaced by their relatives during Krox20 induction in myelinating Schwann cells...
- Hirano S, Anuradha C, Kanno S. Transcription of krox-20/egr-2 is upregulated after exposure to fibrous particles and adhesion in rat alveolar macrophages. Am J Respir Cell Mol Biol. 2000;23:313-9 pubmed..These results suggest that both krox-20/egr-2 and krox-20H1 are implicated in adhesion and phagocytosis, and that the expression of krox-20 may reflect interaction with foreign substances and adhesion in alveolar macrophages. ..
- Hu T, Gimferrer I, Simmons A, WIEST D, Alberola Ila J. The Ras/MAPK pathway is required for generation of iNKT cells. PLoS ONE. 2011;6:e19890 pubmed publisher..Interestingly our results also show that there are differences in the contributions of several of these molecules to the development of iNKT and conventional ?? T cells. ..
- Li S, Symonds A, Zhu B, Liu M, Raymond M, Miao T, et al. Early growth response gene-2 (Egr-2) regulates the development of B and T cells. PLoS ONE. 2011;6:e18498 pubmed publisher..Our results demonstrate that Egr-2 expressed in restricted stages of lymphocyte development plays a dynamic, but similar role for the development of T, NKT and B cells. ..
- Sham M, Vesque C, Nonchev S, Marshall H, Frain M, Gupta R, et al. The zinc finger gene Krox20 regulates HoxB2 (Hox2.8) during hindbrain segmentation. Cell. 1993;72:183-96 pubmed..These data demonstrate that Krox20 is a part of the upstream transcriptional cascade that directly regulates HoxB2 expression during hindbrain segmentation. ..
- Jones E, Lopez Anido C, Srinivasan R, Krueger C, Chang L, Nagarajan R, et al. Regulation of the PMP22 gene through an intronic enhancer. J Neurosci. 2011;31:4242-50 pubmed publisher..Overall, these data show that Egr2 and Sox10 activity are directly involved in mediating the developmental induction of Pmp22 expression. ..
- DeSteno D, Schmauss C. Induction of early growth response gene 2 expression in the forebrain of mice performing an attention-set-shifting task. Neuroscience. 2008;152:417-28 pubmed publisher..These findings suggest a specific role of egr-2-mediated transcriptional activation in cognitive functions associated with attention. ..
- Jang S, Leblanc S, Roopra A, Wrabetz L, Svaren J. In vivo detection of Egr2 binding to target genes during peripheral nerve myelination. J Neurochem. 2006;98:1678-87 pubmed..Application of chromatin immunoprecipitation analysis to myelination in vivo will prove to be a valuable asset in assaying transcription factor binding and chromatin modifications during activation of myelin genes. ..
- Levi G, Topilko P, Schneider Maunoury S, Lasagna M, Mantero S, Cancedda R, et al. Defective bone formation in Krox-20 mutant mice. Development. 1996;122:113-20 pubmed
- Helmbacher F, Pujades C, Desmarquet C, Frain M, Rijli F, Chambon P, et al. Hoxa1 and Krox-20 synergize to control the development of rhombomere 3. Development. 1998;125:4739-48 pubmed..In addition, these data suggest that the control of the development of r3 may not be autonomous but dependent on interactions with Hoxa1-expressing cells. ..
- Zorick T, Syroid D, Brown A, Gridley T, Lemke G. Krox-20 controls SCIP expression, cell cycle exit and susceptibility to apoptosis in developing myelinating Schwann cells. Development. 1999;126:1397-406 pubmed..These data demonstrate that the loss of Krox-20 in myelinating Schwann cells arrests differentiation at the promyelinating stage, as assessed by SCIP expression, mitotic activity and susceptibility to apoptosis. ..
- Voiculescu O, Charnay P, Schneider Maunoury S. Expression pattern of a Krox-20/Cre knock-in allele in the developing hindbrain, bones, and peripheral nervous system. Genesis. 2000;26:123-6 pubmed
- Grose R, Harris B, Cooper L, Topilko P, Martin P. Immediate early genes krox-24 and krox-20 are rapidly up-regulated after wounding in the embryonic and adult mouse. Dev Dyn. 2002;223:371-8 pubmed..Despite the dramatic up-regulation of these genes in response to injury, our studies reveal that neither of them on their own is essential for repair. ..
- Leclerc N, Noh T, Cogan J, Samarawickrama D, Smith E, Frenkel B. Opposing effects of glucocorticoids and Wnt signaling on Krox20 and mineral deposition in osteoblast cultures. J Cell Biochem. 2008;103:1938-51 pubmed..These findings are consistent with a role for Krox20 in osteoblast function and suggest that this transcription factor may contribute to the opposing effects of GCs and Wnt signaling on bone formation. ..
- Ghislain J, Desmarquet Trin Dinh C, Jaegle M, Meijer D, Charnay P, Frain M. Characterisation of cis-acting sequences reveals a biphasic, axon-dependent regulation of Krox20 during Schwann cell development. Development. 2002;129:155-66 pubmed..In addition, they provide insight into the complexity of the transcription factor regulatory network controlling myelination. ..
- Gilardi P, Schneider Maunoury S, Charnay P. Krox-20: a candidate gene for the regulation of pattern formation in the hindbrain. Biochimie. 1991;73:85-91 pubmed..The possible interactions between Krox-20 and homeobox containing genes as well as the search for other members of the network will be discussed. ..
- Bellone E, Di Maria E, Soriani S, Varese A, Doria L, Ajmar F, et al. A novel mutation (D305V) in the early growth response 2 gene is associated with severe Charcot-Marie-Tooth type 1 disease. Hum Mutat. 1999;14:353-4 pubmed..The finding of a novel EGR2 mutation associated with a different phenotype confirms that peripheral neuropathies represent a continuum spectrum of related disorders due to an underlying defect in myelination. ..
- He Y, Kim J, Dupree J, Tewari A, MELENDEZ VASQUEZ C, Svaren J, et al. Yy1 as a molecular link between neuregulin and transcriptional modulation of peripheral myelination. Nat Neurosci. 2010;13:1472-80 pubmed publisher..In addition, neuregulin-induced phosphorylation of YY1 was required for transcriptional activation of Egr2. Thus, YY1 emerges as an important activator of peripheral myelination that links neuregulin signaling with Egr2 expression. ..
- Yun B, Anderegg A, Menichella D, Wrabetz L, Feltri M, Awatramani R. MicroRNA-deficient Schwann cells display congenital hypomyelination. J Neurosci. 2010;30:7722-8 pubmed publisher..In SC differentiation, this is particularly relevant in the key developmental transition from a promyelinating to myelinating SC. ..
- Kao S, Wu H, Xie J, Chang C, Ranish J, Graef I, et al. Calcineurin/NFAT signaling is required for neuregulin-regulated Schwann cell differentiation. Science. 2009;323:651-4 pubmed publisher..Our studies demonstrate that calcineurin and NFAT are essential for neuregulin and ErbB signaling, neural crest diversification, and differentiation of Schwann cells. ..
- Unoki M, Nakamura Y. Methylation at CpG islands in intron 1 of EGR2 confers enhancer-like activity. FEBS Lett. 2003;554:67-72 pubmed..Moreover, reporter gene experiments revealed that methylated intron 1 had somehow conferred enhancer-like activity. The data imply the existence of a previously unsuspected mechanism of gene expression regulation. ..
- Le N, Nagarajan R, Wang J, Svaren J, LaPash C, Araki T, et al. Nab proteins are essential for peripheral nervous system myelination. Nat Neurosci. 2005;8:932-40 pubmed
- Lauritsen J, Kurella S, Lee S, Lefebvre J, Rhodes M, Alberola Ila J, et al. Egr2 is required for Bcl-2 induction during positive selection. J Immunol. 2008;181:7778-85 pubmed..Taken together, these data suggest that Egr2 plays a central role in the up-regulation of the survival molecule Bcl-2 during positive selection. ..
- Ghislain J, Charnay P. Control of myelination in Schwann cells: a Krox20 cis-regulatory element integrates Oct6, Brn2 and Sox10 activities. EMBO Rep. 2006;7:52-8 pubmed
- Chomette D, Frain M, Cereghini S, Charnay P, Ghislain J. Krox20 hindbrain cis-regulatory landscape: interplay between multiple long-range initiation and autoregulatory elements. Development. 2006;133:1253-62 pubmed..Together, our studies provide a basis for a model of the molecular mechanisms controlling Krox20 expression in the developing hindbrain and neural crest. ..
- Decker L, Desmarquet Trin Dinh C, Taillebourg E, Ghislain J, Vallat J, Charnay P. Peripheral myelin maintenance is a dynamic process requiring constant Krox20 expression. J Neurosci. 2006;26:9771-9 pubmed..Furthermore, myelin maintenance appears as a very dynamic process in which Krox20 may constitute a molecular switch between Schwann cell myelination and demyelination programs. ..
- Guennoun R, Benmessahel Y, Delespierre B, Gouézou M, Rajkowski K, Baulieu E, et al. Progesterone stimulates Krox-20 gene expression in Schwann cells. Brain Res Mol Brain Res. 2001;90:75-82 pubmed..As Krox-20 is a necessary step for the initiation of myelin formation in peripheral nerves, its stimulation by progesterone suggests an important signalling function for this steroid in myelination. ..
- Taillebourg E, Buart S, Charnay P. Conditional, floxed allele of the Krox20 gene. Genesis. 2002;32:112-3 pubmed
- Mechta Grigoriou F, Garel S, Charnay P. Nab proteins mediate a negative feedback loop controlling Krox-20 activity in the developing hindbrain. Development. 2000;127:119-28 pubmed..Taken together, these data indicate that Krox-20 positively regulates the expression of its own antagonists and raise the possibility that this negative feedback regulatory loop may play a role in the control of hindbrain development. ..