HGNC Approved Gene Symbol: EGR3
Cytogenetic location: 8p21.3 Genomic coordinates (GRCh38): 8:22,687,659-22,693,480 (from NCBI)
Daily rhythms of biologic activity, manifested by forms as diverse as cyanobacteria, fungi, plants, and animals, are driven by self-sustaining, endogenous oscillators called circadian clocks, which typically run with an intrinsic period that is close to, but not exactly, 24 hours (Morris et al., 1998). Under natural conditions, circadian clocks become precisely entrained to the 24-hour light-dark cycle because exposure to light at certain times induces a phase shift of the clock. Entrainment to light-dark cycles ensures that the clock adopts a specific and stable phase relation to the natural day, setting the clock to local time and enabling the organism to anticipate daily environmental events. In mammals, the circadian clock that drives daily rhythms of behavioral activity is located within the suprachiasmatic nucleus (SCN) of the hypothalamus. Entrainment of the clock to light-dark cycles is mediated by photoreceptors in the retina, and light information is conveyed directly from the retina to the SCN by the retinohypothalamic tract. Although the molecular basis of entrainment to light-dark cycles in mammals is unknown, the process probably involves light- and clock-dependent transcriptional regulation within the SCN (Takahashi, 1995). When a rodent kept in constant darkness is exposed to a brief light pulse during the subjective night, a time when the clock responds to light with a phase shift, 5 known early-response genes are specifically induced within the SCN: FOS (164810), FOSB (164772), JUNB (165161), NGFIA (EGR1; 128990), and nur77 (see 139139) (Morris et al., 1998). The genes are not induced by exposure to light during the subjective day, a time when the clock is not phase-shifted by light. These and related experiments strongly suggested that induction of genes in the SCN by light is an intermediate step in a pathway mediating entrainment of the clock to light-dark cycles. They further suggested that gating of this induction by the clock contributes to the restriction of phase-shifting by light to certain times, a feature that is essential for achieving stable entrainment.
Studying Syrian hamsters, Morris et al. (1998) used a cDNA subtraction method based on genomic representational difference analysis (RDA) to identify genes induced in the SCN by light. They found 4 clones that corresponded to genes induced specifically in the SCN by light, all of which showed gating of induction by the circadian clock. Among these genes were FOS and nur77, 2 of the 5 early-response genes known to be induced in the SCN by light, and EGR3, a zinc finger transcription factor not previously identified in the SCN. In contrast to known examples, EGR3 induction by light was restricted to the ventral SCN, a structure implicated in entrainment.
The human EGR3 gene was described by Patwardhan et al. (1991) as predicting a 387-amino acid protein containing 3 C2H2 zinc fingers nearly identical to those of EGR1 and EGR2. The gene was known to be induced in various brain regions in response to stress or following focal brain injury. Morris et al. (1998) stated that, in the SCN, it probably participates in the transcriptional regulation of genes in response to retinal input, as had been proposed for FOS.
Using microarray, RT-PCR, and computer analyses, Safford et al. (2005) found that Egr2 (129010) and Egr3 were associated with induction of anergy in mouse T cells, as measured by inhibition of Il2 (147680) production. Overexpression of Egr2 or Egr3 inhibited Il2 production equivalently. Although Egr2 -/- mice died perinatally, Egr3 -/- mice were resistant to peptide-induced immunologic tolerance. Safford et al. (2005) concluded that EGR2 and EGR3 are involved in promoting a T-cell receptor-induced negative regulatory genetic program.
The EGR3 gene has a single intron (Patwardhan et al., 1991).
Patwardhan et al. (1991) mapped the EGR3 gene to 8p23-p21 by radiolabeled in situ hybridization.
Muscle spindles are skeletal muscle sensory organs that provide axial and limb position information (proprioception) to the central nervous system. Spindles consist of encapsulated muscle fibers (intrafusal fibers) that are innervated by specialized motor and sensory axons. Tourtellotte and Milbrandt (1998) found that mice rendered deficient in Egr3 by gene targeting had gait ataxia, increased frequency of perinatal mortality, scoliosis, resting tremors, and ptosis. Although extrafusal skeletal muscle fibers appeared normal, Egr3-deficient animals lacked muscle spindles, a finding that is consistent with their profound gait ataxia. Egr3 was highly expressed in developing muscle spindles, but not in IIa afferent neurons or their terminals during developmental periods that coincided with the induction of spindle morphogenesis by sensory afferent axons. These results indicated that type I myotubes are dependent upon Egr3-mediated transcription for proper spindle development.
Morris, M. E., Viswanathan, N., Kuhlman, S., Davis, F. C., Weitz, C. J. A screen for genes induced in the suprachiasmatic nucleus by light. Science 279: 1544-1547, 1998. [PubMed: 9488654] [Full Text: https://doi.org/10.1126/science.279.5356.1544]
Patwardhan, S., Gashler, A., Siegel, M. G., Chang, L. C., Joseph, L. J., Shows, T. B., Le Beau, M. M., Sukhatme, V. P. EGR3, a novel member of the Egr family of genes encoding immediate-early transcription factors. Oncogene 6: 917-928, 1991. [PubMed: 1906159]
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. Egr-2 and Egr-3 are negative regulators of T cell activation. Nature Immun. 6: 472-480, 2005. Note: Erratum: Nature Immun. 6: 737 only, 2005. [PubMed: 15834410] [Full Text: https://doi.org/10.1038/ni1193]
Takahashi, J. S. Molecular neurobiology and genetics of circadian rhythms in mammals. Annu. Rev. Neurosci. 18: 531-553, 1995. [PubMed: 7605073] [Full Text: https://doi.org/10.1146/annurev.ne.18.030195.002531]
Tourtellotte, W. G., Milbrandt, J. Sensory ataxia and muscle spindle agenesis in mice lacking the transcription factor Egr3. Nature Genet. 20: 87-91, 1998. [PubMed: 9731539] [Full Text: https://doi.org/10.1038/1757]