Inducible cAMP early repressor (ICER) and brain functions

Abstract

The inducible cAMP early repressor (ICER) is an endogenous repressor of cAMP-responsive element (CRE)-mediated gene transcription and belongs to the CRE-binding protein (CREB)/CRE modulator (CREM)/activating transcription factor 1 (ATF-1) gene family. ICER plays an important role in regulating the neuroendocrine system and the circadian rhythm. Other aspects of ICER function have recently attracted heightened attention. Being a natural inducible CREB antagonist, and more broadly, an inducible repressor of CRE-mediated gene transcription, ICER regulates long-lasting plastic changes that occur in the brain in response to incoming stimulation. This review will bring together data on ICER and its functions in the brain, with a special emphasis on recent findings highlighting the involvement of ICER in the regulation of long-term plasticity underlying learning and memory.

Fig. 1

Schematic representation of the gene encoding CREM/ICER. a The intron/exon structure of the CREM/ICER gene. Also shown are CREM promoters (P1, P3, and P4); ICER promoter (P2); glutamine-rich domains (Q1 and Q2); kinase-inducible domain (P-Box); and DNA-binding domains (DBD I and DBD II) of the ICER gene, containing leucine zipper and basic regions (bZIP). ATG, initiation methionine; TAA and TAG, stop codons. b Schematic mRNA structure of four ICER isoforms and corresponding exons. ICER I mRNA contains sequences encoding both DBD I and II, but the stop codon located in the carboxyl terminus of DBD I prevents insertion of DBD II into the protein

Fig. 2

Fear conditioning in ICER mutant mice. Conditioned freezing to tone and context was compared in ICER-overexpressing (OE) transgenic mice (TG+) and their non-TG littermates (TG−; a), in ICER-knockout (KO) mice and their wild-type (WT) littermates after a standard conditioning protocol (b), and in ICER-KO mice and WT littermates after a weak conditioning protocol (c). a No difference was observed between non-TG mice and ICER-OE mice 1 h after conditioning (1 h tone). However, 24 h (24 h tone) and 48 h (48 h context) after conditioning, tone-dependent and context-dependent freezing were significantly attenuated in ICER-OE mice. b After being subjected to a standard conditioning protocol, ICER-KO mice and WT littermates exhibited similar freezing levels during the tone-dependent tests performed 1 h (1 h tone) and 24 h (24 h tone) after conditioning and during the context-dependent test (48-h context). c After being subjected to a weak conditioning protocol, there was no significant difference in conditioned freezing between ICER-KO and WT mice 1 h after conditioning (1 h tone). However, ICER-KO mice showed increased freezing during both pre-tone and tone presentation in the tone-dependent test performed 24 h after conditioning (24 h tone). Context-dependent freezing in ICER-KO mice was also enhanced (48 h context). Data are means ± SEM; number of animals per group are in parentheses. *p < 0.05; **p < 0.01; ***p < 0.001 compared to non-TG or WT littermates (with modifications from [21])

Fig. 3

Simplified schematic diagram of ICER acting as a regulator of long-term plasticity. In wild-type mice, incoming stimuli activate protein kinases and activated kinases phosphorylate CREB. Phosphorylated CREB activates CRE-containing gene transcription. Phosphorylated CREB also activates P2 promoter and initiates ICER transcription. ICER is a transcription repressor, and after reaching a certain concentration, starts to suppress CRE-dependent activation of gene expression, including its own expression (through the formation of ICER homodimers or ICER-CREB heterodimers that bind to CREs and block transcription). In ICER-OE mice, suppression of CRE-mediated gene transcription is enhanced by a constitutively available excess amount of ICER. In ICER-KO mice, lack of ICER-mediated suppression results in a prolonged activation of CRE-mediated gene transcription. Accumulated gene products that result from the transcription-translation of the gene are indicated as filled squares; ICER proteins are indicated as crosses; the transcription activator CREB is indicated by gray filled circles. P, phosphate group; P2, ICER promoter in the CREM/ICER gene; CRE, CRE-containing promoters (figure with modifications was adapted from [21])