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PMID: 19365618 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Induction of early growth response-1 mediates microglia activation in vitro but is dispensable in vivo.

Neuromolecular medicine ·Vol. 11 ·No. 2 ·2009-00-00 ·Pages 87-96

Langmann T, Ebert S, Walczak Y, Weigelt K, Ehrengruber MU, Stiewe T, Weber BH

Abstract

We have previously identified activation of microglia and induction of the early growth response gene 1 (Egr1) in the retina of retinoschisin-deficient (Rs1h(-/Y)) mice. We hypothesized that microglial expression of Egr1 might support retinal microgliosis. To test this, Egr1 transcript levels were determined in RNAs isolated from early postnatal retinas and primary microglia from Rs1h(-/Y) mice and wild-type controls. Egr1 mRNA expression was strongly induced in retinoschisin-deficient retinas as well as in ex vivo isolated microglia. Increased microglial Egr1 protein expression was concordantly detected in retinal sections of Rs1h(-/Y) mice using immunohistochemistry. Prominent activation-dependent Egr1 mRNA and protein expression was also confirmed in murine BV-2 microglia. Using binding site prediction and chromatin immunoprecipitation, we identified that the Egr1 promoter itself and the microglial marker genes Clec7a and Caspase11 are direct transcriptional targets of Egr1. Over-expression of Egr1 in BV-2 cells by adenoviral infection promoted Clec7a and Caspase11 mRNA synthesis, whereas expression of the Egr1 repressor NAB2 blocked the transcription of these genes. To analyze whether Egr1 was absolutely required for microglial marker expression in vivo, transcript levels were quantified in Rs1h(-/Y)/Egr1(-/-) retinas. No significant differences in activation marker expression could be measured in retinal tissue from Rs1h(-/Y)/Egr1(-/-) mice compared to Rs1h(-/Y) mice, suggesting that lack of Egr1 does not impair transcription of microglia genes in vivo. Taken together, our findings suggest that increased Egr1 expression is present in activated retinal microglia and contributes to their activation. However, up-regulation of Egr1 is not absolutely required for retinal microglia activation in vivo.

MeSH Terms
Animals Biomarkers/metabolism Caspases/metabolism Caspases, Initiator Cell Adhesion Molecules/genetics,metabolism Cells, Cultured Early Growth Response Protein 1/genetics,metabolism Eye Proteins/genetics,metabolism Humans Mice Mice, Inbred C57BL Mice, Knockout Microglia/cytology,metabolism Recombinant Fusion Proteins/genetics,metabolism Retina/cytology,metabolism
Chemicals
Biomarkers Cell Adhesion Molecules Early Growth Response Protein 1 Eye Proteins RS1 protein, mouse Recombinant Fusion Proteins Casp4 protein, mouse Caspases Caspases, Initiator
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Langmann Thomas
Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93042, Regensburg, Germany. [email protected]
Ebert Stefanie
Walczak Yana
Weigelt Karin
Ehrengruber Markus U
Stiewe Thorsten
Weber Bernhard H F
References (54)
54 references, click to expand
  1. Inactivation of the murine X-linked juvenile retinoschisis gene, Rs1h, suggests a role of retinoschisin in retinal cell layer organization and synaptic structure.
    Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6222-7 PMID: 11983912
  2. Mitogen-activated protein kinase-signaling stimulates Müller glia to proliferate in acutely damaged chicken retina.
    Glia. 2009 Jan 15;57(2):166-81 PMID: 18709648
  3. Distinct intragraft response pattern in relation to graft size in liver transplantation.
    Transplantation. 2003 Mar 15;75(5):673-8 PMID: 12640308
  4. Regulation of life and death by the zinc finger transcription factor Egr-1.
    J Cell Physiol. 2002 Dec;193(3):287-92 PMID: 12384981
  5. Microglia activation in retinal degeneration.
    J Leukoc Biol. 2007 Jun;81(6):1345-51 PMID: 17405851
  6. Transcriptional activity of the zinc finger protein NGFI-A is influenced by its interaction with a cellular factor.
    Mol Cell Biol. 1993 Nov;13(11):6858-65 PMID: 8413279
  7. Early growth response protein 1 (Egr-1): prototype of a zinc-finger family of transcription factors.
    Prog Nucleic Acid Res Mol Biol. 1995;50:191-224 PMID: 7754034
  8. Transcription factor early growth response-1 induction mediates inflammatory gene expression and brain damage following transient focal ischemia.
    J Neurochem. 2008 May;105(4):1313-24 PMID: 18208539
  9. Early growth response factor 1: a pleiotropic mediator of inducible gene expression.
    J Mol Med (Berl). 1998 Aug;76(9):613-6 PMID: 9725763
  10. Early growth response-1 promotes atherogenesis: mice deficient in early growth response-1 and apolipoprotein E display decreased atherosclerosis and vascular inflammation.
    Circ Res. 2004 Feb 20;94(3):333-9 PMID: 14670837
  11. Microglia-targeted pharmacotherapy in retinal neurodegenerative diseases.
    Curr Drug Targets. 2004 Oct;5(7):619-27 PMID: 15473251
  12. The EGR family of transcription-regulatory factors: progress at the interface of molecular and systems neuroscience.
    Trends Neurosci. 1999 Apr;22(4):167-73 PMID: 10203854
  13. Protein kinase C beta/early growth response-1 pathway: a key player in ischemia, atherosclerosis, and restenosis.
    J Am Coll Cardiol. 2006 Nov 7;48(9 Suppl 1):A47-55 PMID: 17084284
  14. The zinc finger transcription factor Egr-1 potentiates macrophage differentiation of hematopoietic cells.
    Mol Cell Biol. 1995 Oct;15(10):5499-507 PMID: 7565701
  15. Recombinant adenovirus-mediated expression in nervous system of genes coding for ion channels and other molecules involved in synaptic function.
    Methods Enzymol. 1998;293:483-503 PMID: 9711625
  16. Microarray analysis of changes in mRNA levels in the rat retina after experimental elevation of intraocular pressure.
    Invest Ophthalmol Vis Sci. 2004 Apr;45(4):1247-58 PMID: 15037594
  17. Extinguishing Egr-1-dependent inflammatory and thrombotic cascades after lung transplantation.
    FASEB J. 2001 Dec;15(14):2757-9 PMID: 11606484
  18. Egr transcription factors in the nervous system.
    Neurochem Int. 1997 Oct;31(4):477-510; discussion 517-6 PMID: 9307998
  19. Control of myeloid activity during retinal inflammation.
    J Leukoc Biol. 2003 Aug;74(2):161-6 PMID: 12885931
  20. Early growth response transcriptional regulators are dispensable for macrophage differentiation.
    J Immunol. 2007 Mar 1;178(5):3038-47 PMID: 17312150
  21. NALP inflammasomes: a central role in innate immunity.
    Semin Immunopathol. 2007 Sep;29(3):213-29 PMID: 17703304
  22. Pancreatic gene expression during the initiation of acute pancreatitis: identification of EGR-1 as a key regulator.
    Physiol Genomics. 2003 Jun 24;14(1):59-72 PMID: 12709512
  23. The zinc finger transcription factor Egr-1 is essential for and restricts differentiation along the macrophage lineage.
    Cell. 1993 Jan 29;72(2):197-209 PMID: 7678779
  24. Novel mutants of NAB corepressors enhance activation by Egr transactivators.
    EMBO J. 1998 Oct 15;17(20):6010-9 PMID: 9774344
  25. Early growth response gene 1 stimulates development of hematopoietic progenitor cells along the macrophage lineage at the expense of the granulocyte and erythroid lineages.
    Blood. 2001 Mar 1;97(5):1298-305 PMID: 11222373
  26. Light damage induced changes in mouse retinal gene expression.
    Exp Eye Res. 2004 Aug;79(2):239-47 PMID: 15325571
  27. Microglia as neuroprotective, immunocompetent cells of the CNS.
    Glia. 2002 Nov;40(2):133-9 PMID: 12379901
  28. Microglia as a source and target of cytokines.
    Glia. 2002 Nov;40(2):140-55 PMID: 12379902
  29. P-selectin and intercellular adhesion molecule-1 expression after focal brain ischemia and reperfusion.
    Stroke. 1994 Jan;25(1):202-11 PMID: 7505494
  30. Egr-1 target genes in human endothelial cells identified by microarray analysis.
    Gene. 2003 Oct 2;315:33-41 PMID: 14557062
  31. Ischemic preconditioning alters the pattern of gene expression changes in response to full retinal ischemia.
    Mol Vis. 2007 Oct 05;13:1892-901 PMID: 17960128
  32. Temporal changes in gene expression after injury in the rat retina.
    Invest Ophthalmol Vis Sci. 2004 Aug;45(8):2737-46 PMID: 15277499
  33. Genome-wide expression profiling of the retinoschisin-deficient retina in early postnatal mouse development.
    Invest Ophthalmol Vis Sci. 2007 Feb;48(2):891-900 PMID: 17251492
  34. Beta-glucan activates microglia without inducing cytokine production in Dectin-1-dependent manner.
    J Immunol. 2008 Mar 1;180(5):2777-85 PMID: 18292498
  35. Growth and differentiation proceeds normally in cells deficient in the immediate early gene NGFI-A.
    J Biol Chem. 1995 Apr 28;270(17):9971-7 PMID: 7730380
  36. Modulation of early growth response (EGR) transcription factor-dependent gene expression by using recombinant adenovirus.
    Gene. 2000 Nov 27;258(1-2):63-9 PMID: 11111043
  37. NAB2, a corepressor of NGFI-A (Egr-1) and Krox20, is induced by proliferative and differentiative stimuli.
    Mol Cell Biol. 1996 Jul;16(7):3545-53 PMID: 8668170
  38. Distribution, markers, and functions of retinal microglia.
    Ocul Immunol Inflamm. 2002 Mar;10(1):27-39 PMID: 12461701
  39. Identification of NAB1, a repressor of NGFI-A- and Krox20-mediated transcription.
    Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6873-7 PMID: 7624335
  40. HGF induces fibronectin matrix synthesis in melanoma cells through MAP kinase-dependent signaling pathway and induction of Egr-1.
    Oncogene. 2005 Feb 17;24(8):1423-33 PMID: 15608673
  41. Lipopolysaccharide induction of the tumor necrosis factor-alpha promoter in human monocytic cells. Regulation by Egr-1, c-Jun, and NF-kappaB transcription factors.
    J Biol Chem. 1997 Jul 11;272(28):17795-801 PMID: 9211933
  42. Unimpaired macrophage differentiation and activation in mice lacking the zinc finger transplantation factor NGFI-A (EGR1).
    Mol Cell Biol. 1996 Aug;16(8):4566-72 PMID: 8754857
  43. Activated microglia in human retinitis pigmentosa, late-onset retinal degeneration, and age-related macular degeneration.
    Exp Eye Res. 2003 Apr;76(4):463-71 PMID: 12634111
  44. Dap12 expression in activated microglia from retinoschisin-deficient retina and its PU.1-dependent promoter regulation.
    J Leukoc Biol. 2007 Dec;82(6):1564-74 PMID: 17827340
  45. Microarray analysis of retinal gene expression in the DBA/2J model of glaucoma.
    Invest Ophthalmol Vis Sci. 2006 Mar;47(3):977-85 PMID: 16505032
  46. Egr-1 upregulates the Alzheimer's disease presenilin-2 gene in neuronal cells.
    Gene. 2003 Oct 30;318:113-24 PMID: 14585504
  47. Microglial control of neuronal death and synaptic properties.
    Glia. 2007 Feb;55(3):233-8 PMID: 17106878
  48. DNA-binding specificity of NGFI-A and related zinc finger transcription factors.
    Mol Cell Biol. 1995 Apr;15(4):2275-87 PMID: 7891721
  49. Early growth response factor-1 is a critical transcriptional mediator of peroxisome proliferator-activated receptor-gamma 1 gene expression in human aortic smooth muscle cells.
    J Biol Chem. 2002 Jul 26;277(30):26808-14 PMID: 12011097
  50. Nab1, a corepressor of NGFI-A (Egr-1), contains an active transcriptional repression domain.
    Mol Cell Biol. 1998 Jan;18(1):512-24 PMID: 9418898
  51. Mechanism of amyloid peptide induced CCR5 expression in monocytes and its inhibition by siRNA for Egr-1.
    Am J Physiol Cell Physiol. 2005 Aug;289(2):C264-76 PMID: 15743889
  52. Identification and characterization of Chlamydia pneumoniae-specific proteins that activate tumor necrosis factor alpha production in RAW 264.7 murine macrophages.
    Infect Immun. 2008 Apr;76(4):1558-64 PMID: 18227157
  53. Posttranscriptional regulation of the immediate-early gene EGR1 by light in the mouse retina.
    Eur J Neurosci. 2004 Dec;20(12):3371-7 PMID: 15610169
  54. Immunohistochemical localization of a macrophage-specific antigen in developing mouse retina: phagocytosis of dying neurons and differentiation of microglial cells to form a regular array in the plexiform layers.
    J Cell Biol. 1983 Jul;97(1):253-7 PMID: 6345555
Article Info
Journal
Neuromolecular medicine
Abbr.
Neuromolecular Med
ISSN
1559-1174
DOI
10.1007/s12017-009-8061-6
Email
[email protected]
Published
2009-00-00
Epub
2009-00-14
Pages
87-96
Language
English
Region
United States
NLM ID
101135365
Subset
IM
External Links
PubMed source DOI: 10.1007/s12017-009-8061-6 View journal details
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