Genomic profiling of the neuronal target genes of the plasticity‐related transcription factor – Zif268

Abstract

The later phases of neuronal plasticity are invariably dependent on gene transcription. Induction of the transcription factor Zif268 (Egr-1) in neurones is closely associated with many forms of functional plasticity, yet the neuronal target genes modulated by Zif268 have not been characterized. After transfection of a neuronal cell line with Zif268 we identified genes that show altered expression using high density microarrays. Although some of the genes identified have previously been associated with forms of neuronal plasticity, the majority have not been linked with neuronal plasticity or Zif268 action. Altered expression of a representative sample of the novel target genes was confirmed in Zif268-transfected PC12 neurones, and in in vitro and in vivo models of Zif268-associated neuronal plasticity. In particular, altered expression of the protease inhibitor Cystatin C and the chemokine Cxcl10 was observed in striatal tissue after haloperidol administration. Surprisingly, the group of identified genes is enriched for components of the proteasome and the major histocompatibility complex. Our findings suggest that altered expression of these genes following Zif268 induction may be a key component of long lasting plasticity in the CNS.

Regulation of the Neuronal Proteasome by Zif268 (Egr1)

“…In peripheral cells, Zif268 mediates transcriptional suppression or induction of various genes (Cao et al, 1993;Liu et al, 1996;Beckmann and Wilce, 1997;Thottassery et al, 1999;Bahouth et al, 2002;Virolle et al, 2003;Zhang and Liu, 2003;Wang et al, 2005). We have recently identified candidate target genes of Zif268 in neurons (James et al, 2005). A remarkable finding was that many of the genes identified encoded either components of the proteasome or proteins with functions closely allied to the proteasome.…”

Zif268 / Egr1 gain of function facilitates hippocampal synaptic plasticity and long-term spatial recognition memory

“…Although the precise mechanisms by which Zif268 overexpression facilitates LTP and long-term spatial recognition memory are unknown, the increased neuronal capacity to regulate Zif268 downstream gene programmes may be one mechanism underlying the enhancement of LTP and the facilitation of the formation of a long-term recognition memory. Although several potential Zif268 target genes bearing ERE consensus sequences on their promoter regions have been suggested [23,25,36], characterizing the selective gene programmes controlled by Zif268 in relation to learning and memory remains a challenge for future research.…”

“…We selected two downstream targets of Zif268, synapsin II and the proteasome 20S b-subunit PSMB9 (LMP2), a subunit of the proteasome belonging to the multisubunit catalytic core of the proteolytic machinery [22], to examine their expression following LTP. Both genes possess Zif268 binding sites on their promoter regions [23][24][25]. Dentate gyrus tissue was processed for western blotting as described previously [26], using anti-synapsin II (1/15000 in TBST BSA 5%, Abcam, France) and anti-PSMB9 (1/1000 in TBST BSA 5%, Abcam, France) antibodies.…”

Upregulation of the Neuron-Specific K+/Cl−Cotransporter Expression by Transcription Factor Early Growth Response 4

“…Of the four Egr proteins, Egr4 has the most neural-specific pattern of expression, and in rats its expression increases gradually during the first 3 postnatal weeks of development (Crosby et al, 1992). However, in contrast to other Egr proteins like Egr1, which is known to be involved in many processes of neuronal plasticity (Knapska and Kaczmarek, 2004;Li et al, 2005) and in the regulation of several neuralspecific genes (James et al, 2005), the role of Egr4 in the regulation of neuronal genes remains elusive (Tourtellotte et al, , 2000.…”