Disease relevance of Egr3

• Egr3-/- mice develop gait ataxia, scoliosis, resting tremors, and ptosis, suggesting a defect in proprioception [1].
• Egr3-deficient mice have severe sympathetic target tissue innervation abnormalities and profound physiological dysautonomia [2].

High impact information on Egr3

• Thus, transient induction of Egr3 delays the effects of RORgammat and enables pre-TCR signaling to induce both proliferation and gene rearrangement [3].
• Conversely, T cells from Egr3(-/-) mice had lower expression of Cbl-b and were resistant to in vivo peptide-induced tolerance [4].
• Egr-2 and Egr-3 are negative regulators of T cell activation [4].
• Recent molecular studies have identified the gonadotropin subunit, luteinizing hormone beta, as an EGR1-regulated gene in vivo and uncovered an essential role for EGR3 in muscle-spindle development [5].
• We have monitored the expression of three transcription factors, Egr3, Pea3, and Erm, that delineate early muscle spindle development in an assay of muscle spindle-inducing signals [6].

Biological context of Egr3

• The transcription factor Egr3 modulates sensory axon-myotube interactions during muscle spindle morphogenesis [7].
• In Egr3-deficient mice, myotubes received Ia afferent innervation and assembled normally into spindles during embryogenesis [7].
• Egr3 is a transcriptional regulator that contains a zinc-finger DNA binding domain [8].
• We have also generated transgenic mice that express high levels of Egr3 constitutively, and when these mice are bred onto a Rag1(-/-) background they exhibit increased proliferation in the absence of stimulation and have pre-TCR alpha-chain and CD25 down-regulation, as well as increased Calpha expression [8].
• Constitutive transgenic expression of Egr3 in thymocytes increases apoptosis among DP cells and shortens their survival in vitro [9].

Anatomical context of Egr3

• In wild type mice, Egr3 was expressed in developing myotubes shortly after they were innervated by Ia afferents and its expression was controlled by innervation because it dissipated following nerve transection [7].
• As germ cells form longer interconnected chains (incomplete cytokinesis), the Egr3 signal disappears coincident with a loss of stem cell activity [10].

Associations of Egr3 with chemical compounds

• Constitutive transgenic expression of Egr3 results in poor expression of Bcl-x(L) and the thymic isoform of retinoic acid receptor-related orphan receptor gamma (RORgammat) in DP thymocytes, two molecules that are required in DP cells for normal life span [9].
• Cyclosporin A-sensitive transcription factor Egr-3 regulates Fas ligand expression [11].
• Despite their sensitivity to this therapeutic effect of clozapine, Egr3-/- mice display a marked resistance to the sedating effects of acute clozapine compared with WT littermate controls [12].

Other interactions of Egr3

• NAB1 also represses Krox20 activity, but it does not influence Egr3 or NGFI-G, thus providing a mechanism for the differential regulation of this family of immediate-early transcription factors [13].
• Although overexpressed Egr-1 was ineffective, overexpressed Egr-2 was as potent as Egr-3 in inducing fasL promoter-dependent reporter constructs in T cell hybridomas and HeLa cells, and both up-regulated endogenous fasL mRNA in HeLa cells [14].
• Moreover, slow-developmental myosin heavy chain was not induced in embryonic Egr3-deficient spindles suggesting that impairments in differentiation were present before they could be detected morphologically [7].
• Ectopic expression of Egr-3 but not Sp1 protein in the abnormal DN T cells enhanced fasl promoter activity, suggesting that the Egr but not Sp1 was limiting for fasl gene activation [15].

Analytical, diagnostic and therapeutic context of Egr3

• 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 [4].
• We establish a spermatogonial stem cell index (SSCI) that reliably predicts relative stem cell activity in rat or mouse testis cell cultures, and through the use of an antibody to a robust signal (Egr3) within the index find intense signals in single or paired cells [10].
• Gel shift assays and chromatin immunoprecipitation assays reveal that Egr-1, Egr-3, and NFAT1 present in primary human CD4 T cells are capable of binding this combinatorial site in vitro and in vivo, respectively [16].

References