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Gene Review

Egr2  -  early growth response 2

Mus musculus

Synonyms: E3 SUMO-protein ligase EGR2, EGR-2, Early growth response protein 2, Egr-2, Krox-20, ...
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Disease relevance of Egr2

  • In co-transfection experiments in cultured cells, Krox-20 dramatically activates transcription from the herpes simplex virus thymidine kinase promoter when an oligomer of its binding site is present in cis close to the promoter [1].
  • To investigate its function, we have used homologous recombination to generate mice carrying an in-frame insertion of the E. coli lacZ gene within Krox-20 [2].
  • The newborn (PO) Krox-20-/- mice, in which apneas are ten times longer than in wild-type animals, may be a valuable model for the study of life-threatening apneas during early infancy [3].

High impact information on Egr2


Biological context of Egr2


Anatomical context of Egr2


Associations of Egr2 with chemical compounds

  • DEX strongly repressed Krox20/Egr2 at both the mRNA and the protein level [14].
  • Furthermore, the regulatory role of Krox-20 is not restricted to the control of Hox gene expression, since it is also involved in the activation of a receptor tyrosine kinase gene, Sek-1, in r3 and r5 and in the repression of the follistatin gene in r3 but not in r5 [15].
  • In contrast, the calcineurin inhibitor cyclosporin A, which inhibits DPK cell differentiation as well as positive selection, inhibits expression of Egr-2 and Egr-3, but not Egr-1 [16].
  • Significantly, a major function of Krox-20 is to suppress the c-Jun NH2-terminal protein kinase (JNK)-c-Jun pathway, activation of which is required for both proliferation and death [17].
  • Lower doses of progesterone (10(-9), 10(-8) and 10(-7) M) are also effective in increasing Krox-20 mRNA [18].

Physical interactions of Egr2


Regulatory relationships of Egr2

  • Krox-20 has been shown to directly regulate the Hoxb-2 gene and we wanted to determine if it was involved in regulating multiple Hox genes as a part of its functional role [9].
  • Segmental expression of Hoxa-2 in the hindbrain is directly regulated by Krox-20 [9].
  • Examination of Krox-20 expression at stages as early as E8.5 indicates that Krox-20 fails ever to be expressed in its r5 domain in the homozygous kreisler mutant [21].
  • VIP/PACAP inhibit the expression of Egr2 and 3, but not of Egr1 [22].
  • We propose this as a possible component of the mechanism by which Krox-20 regulates JNK activity during Schwann cell development [17].
  • Mutation of these binding sites allowed us to establish that Krox20 is under the direct transcriptional control of both Meis (presumably Meis2) and Hox/Pbx factors in r3 [23].

Other interactions of Egr2

  • However, a limited area of the hindbrain shows a strong reduction in Hoxb-1 (Hox-2.9) and Krox-20 transcripts, which most likely reflects a marked reduction in size of the former fourth and fifth rhombomeres [8].
  • There was a clear loss of expression in r3, which indicated that Hoxa-2 was downstream of Krox-20 [9].
  • In the mutant hindbrain, the expression domain of kreisler is twice its normal size and the caudal stripe of Krox-20 extends into the presumptive rhombomeres 6 and 7 region [24].
  • The expression domains of Krox-20 and Fgf-3 are also displaced in a rostral direction and the intensity of Fgf-3 hybridization is greatly reduced [25].
  • Analysis of mouse mutants suggests that c-jun expression in these territories is dependent on MafB but independent of the zinc-finger transcription factor Krox20, another essential determinant of r5 development [13].

Analytical, diagnostic and therapeutic context of Egr2

  • Using microarray analysis we have identified here early growth response gene 2 (Egr-2) and Egr-3 as key negative regulators of T cell activation [11].
  • Parallel analysis of the expression of Krox-20 and Hox-1.4 in the neural tube by in situ hybridization revealed no overlap, arguing against direct interactions between these two genes [1].
  • Like Krox-20, Krox-24 is transiently activated in quiescent cells after treatment with fetal bovine serum or purified growth factors [26].
  • Together, these data demonstrate that Krox20 is essential to the generation of alternating odd- and even-numbered territories in the hindbrain and that it acts by coupling the processes of segment formation, cell segregation and specification of regional identity [27].
  • In contrast, exposure to RA at early somite stages results in near-normal rhombomeric segmentation; rhombomeric gene expression domains indicate that only rhombomere 2 has changed its genetic identity to that of rhombomere 4, the other preotic segments showing normal expression patterns for HoxB genes and Krox-20 [28].


  1. The segment-specific gene Krox-20 encodes a transcription factor with binding sites in the promoter region of the Hox-1.4 gene. Chavrier, P., Vesque, C., Galliot, B., Vigneron, M., Dollé, P., Duboule, D., Charnay, P. EMBO J. (1990) [Pubmed]
  2. Disruption of Krox-20 results in alteration of rhombomeres 3 and 5 in the developing hindbrain. Schneider-Maunoury, S., Topilko, P., Seitandou, T., Levi, G., Cohen-Tannoudji, M., Pournin, S., Babinet, C., Charnay, P. Cell (1993) [Pubmed]
  3. Reorganization of pontine rhythmogenic neuronal networks in Krox-20 knockout mice. Jacquin, T.D., Borday, V., Schneider-Maunoury, S., Topilko, P., Ghilini, G., Kato, F., Charnay, P., Champagnat, J. Neuron (1996) [Pubmed]
  4. Retinoic acid alters hindbrain Hox code and induces transformation of rhombomeres 2/3 into a 4/5 identity. Marshall, H., Nonchev, S., Sham, M.H., Muchamore, I., Lumsden, A., Krumlauf, R. Nature (1992) [Pubmed]
  5. Segment-specific expression of a zinc-finger gene in the developing nervous system of the mouse. Wilkinson, D.G., Bhatt, S., Chavrier, P., Bravo, R., Charnay, P. Nature (1989) [Pubmed]
  6. Perinatal lethality and defects in hindbrain development in mice homozygous for a targeted mutation of the zinc finger gene Krox20. Swiatek, P.J., Gridley, T. Genes Dev. (1993) [Pubmed]
  7. Identification of NAB1, a repressor of NGFI-A- and Krox20-mediated transcription. Russo, M.W., Sevetson, B.R., Milbrandt, J. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  8. Local alterations of Krox-20 and Hox gene expression in the hindbrain suggest lack of rhombomeres 4 and 5 in homozygote null Hoxa-1 (Hox-1.6) mutant embryos. Dollé, P., Lufkin, T., Krumlauf, R., Mark, M., Duboule, D., Chambon, P. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  9. Segmental expression of Hoxa-2 in the hindbrain is directly regulated by Krox-20. Nonchev, S., Vesque, C., Maconochie, M., Seitanidou, T., Ariza-McNaughton, L., Frain, M., Marshall, H., Sham, M.H., Krumlauf, R., Charnay, P. Development (1996) [Pubmed]
  10. Regulation of cholesterol/lipid biosynthetic genes by Egr2/Krox20 during peripheral nerve myelination. Leblanc, S.E., Srinivasan, R., Ferri, C., Mager, G.M., Gillian-Daniel, A.L., Wrabetz, L., Svaren, J. J. Neurochem. (2005) [Pubmed]
  11. Egr-2 and Egr-3 are negative regulators of T cell activation. Safford, M., Collins, S., Lutz, M.A., Allen, A., Huang, C.T., Kowalski, J., Blackford, A., Horton, M.R., Drake, C., Schwartz, R.H., Powell, J.D. Nat. Immunol. (2005) [Pubmed]
  12. Glucocorticoids inhibit osteocalcin transcription in osteoblasts by suppressing Egr2/Krox20-binding enhancer. Leclerc, N., Noh, T., Khokhar, A., Smith, E., Frenkel, B. Arthritis Rheum. (2005) [Pubmed]
  13. c-jun regulation and function in the developing hindbrain. Mechta-Grigoriou, F., Giudicelli, F., Pujades, C., Charnay, P., Yaniv, M. Dev. Biol. (2003) [Pubmed]
  14. Gene expression profiling of glucocorticoid-inhibited osteoblasts. Leclerc, N., Luppen, C.A., Ho, V.V., Nagpal, S., Hacia, J.G., Smith, E., Frenkel, B. J. Mol. Endocrinol. (2004) [Pubmed]
  15. Krox-20 is a key regulator of rhombomere-specific gene expression in the developing hindbrain. Seitanidou, T., Schneider-Maunoury, S., Desmarquet, C., Wilkinson, D.G., Charnay, P. Mech. Dev. (1997) [Pubmed]
  16. Induction of the early growth response (Egr) family of transcription factors during thymic selection. Shao, H., Kono, D.H., Chen, L.Y., Rubin, E.M., Kaye, J. J. Exp. Med. (1997) [Pubmed]
  17. Krox-20 inhibits Jun-NH2-terminal kinase/c-Jun to control Schwann cell proliferation and death. Parkinson, D.B., Bhaskaran, A., Droggiti, A., Dickinson, S., D'Antonio, M., Mirsky, R., Jessen, K.R. J. Cell Biol. (2004) [Pubmed]
  18. Progesterone stimulates Krox-20 gene expression in Schwann cells. Guennoun, R., Benmessahel, Y., Delespierre, B., Gouézou, M., Rajkowski, K.M., Baulieu, E.E., Schumacher, M. Brain Res. Mol. Brain Res. (2001) [Pubmed]
  19. Characterisation of cis-acting sequences reveals a biphasic, axon-dependent regulation of Krox20 during Schwann cell development. Ghislain, J., Desmarquet-Trin-Dinh, C., Jaegle, M., Meijer, D., Charnay, P., Frain, M. Development (2002) [Pubmed]
  20. Hoxb-2 transcriptional activation in rhombomeres 3 and 5 requires an evolutionarily conserved cis-acting element in addition to the Krox-20 binding site. Vesque, C., Maconochie, M., Nonchev, S., Ariza-McNaughton, L., Kuroiwa, A., Charnay, P., Krumlauf, R. EMBO J. (1996) [Pubmed]
  21. The kreisler mouse: a hindbrain segmentation mutant that lacks two rhombomeres. McKay, I.J., Muchamore, I., Krumlauf, R., Maden, M., Lumsden, A., Lewis, J. Development (1994) [Pubmed]
  22. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit expression of Fas ligand in activated T lymphocytes by regulating c-Myc, NF-kappa B, NF-AT, and early growth factors 2/3. Delgado, M., Ganea, D. J. Immunol. (2001) [Pubmed]
  23. Rostral hindbrain patterning involves the direct activation of a Krox20 transcriptional enhancer by Hox/Pbx and Meis factors. Wassef, M.A., Chomette, D., Pouilhe, M., Stedman, A., Havis, E., Desmarquet-Trin Dinh, C., Schneider-Maunoury, S., Gilardi-Hebenstreit, P., Charnay, P., Ghislain, J. Development (2008) [Pubmed]
  24. Key roles of retinoic acid receptors alpha and beta in the patterning of the caudal hindbrain, pharyngeal arches and otocyst in the mouse. Dupé, V., Ghyselinck, N.B., Wendling, O., Chambon, P., Mark, M. Development (1999) [Pubmed]
  25. Altered rhombomere-specific gene expression and hyoid bone differentiation in the mouse segmentation mutant, kreisler (kr). Frohman, M.A., Martin, G.R., Cordes, S.P., Halamek, L.P., Barsh, G.S. Development (1993) [Pubmed]
  26. Two mouse genes encoding potential transcription factors with identical DNA-binding domains are activated by growth factors in cultured cells. Lemaire, P., Revelant, O., Bravo, R., Charnay, P. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  27. Hindbrain patterning: Krox20 couples segmentation and specification of regional identity. Voiculescu, O., Taillebourg, E., Pujades, C., Kress, C., Buart, S., Charnay, P., Schneider-Maunoury, S. Development (2001) [Pubmed]
  28. Exposure to retinoic acid before or after the onset of somitogenesis reveals separate effects on rhombomeric segmentation and 3' HoxB gene expression domains. Wood, H., Pall, G., Morriss-Kay, G. Development (1994) [Pubmed]
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