Elsevier

Progress in Neurobiology

Volume 74, Issue 4, November 2004, Pages 183-211
Progress in Neurobiology

A gene for neuronal plasticity in the mammalian brain: Zif268/Egr-1/NGFI-A/Krox-24/TIS8/ZENK?

https://doi.org/10.1016/j.pneurobio.2004.05.007Get rights and content

Abstract

Zif268 is a transcription regulatory protein, the product of an immediate early gene. Zif268 was originally described as inducible in cell cultures; however, it was later shown to be activated by a variety of stimuli, including ongoing synaptic activity in the adult brain. Recently, mice with experimentally mutated zif268 gene have been obtained and employed in neurobiological research. In this review we present a critical overview of Zif268 expression patterns in the naive brain and following neuronal stimulation as well as functional data with Zif268 mutants. In conclusion, we suggest that Zif268 expression and function should be considered in a context of neuronal activity that is tightly linked to neuronal plasticity.

Introduction

The gene named zif2681 (zinc finger binding protein clone 268) is also called early growth response gene 1 (Egr-1), nerve growth factor-induced gene A (NGFI-A), gene containing sequences homologous to the Drosophila Kr finger probe (Krox-24) and tetradecanoyl phorbol acetate-induced sequence 8 (TIS8). The ambiguity in the nomenclature results from the fact that this gene has been independently identified in different laboratories. Thus, a term ZENK (the acronym of the previous four names) has been coined, and it is used nowadays in parallel with all the other names.

zif268 was initially identified by Lau and Nathans (1987) in mouse fibroblasts, where it was induced by serum and growth factors. At the same time Milbrandt (1987) identified NGFI-A in a screening strategy that aimed at detecting genes induced by NGF (nerve growth factor) in rat PC12 cells.2 These discoveries were quickly followed by several independent descriptions of similar gene sequences from mice, rats and humans (Almendral et al., 1988, Christy et al., 1988, Lemaire et al., 1988, Sukhatme et al., 1988, Tsai-Morris et al., 1988, Arenander et al., 1989, Changelian et al., 1989, Janssen-Timmen et al., 1989, Cao et al., 1990, Lemaire et al., 1990, Suggs et al., 1990).

zif268 belongs to the category of immediate early genes3 (IEG) since it is activated in the absence of de novo protein synthesis (Milbrandt, 1987, Lemaire et al., 1988, Arenander et al., 1989). It codes for a transcription factor protein (Cao et al., 1990, Lemaire et al., 1990, Waters et al., 1990), which has a distinct pattern of expression in the brain (Milbrandt, 1987, Mack et al., 1990, Herdegen et al., 1990, Waters et al., 1990). Acting as a transcription factor, Zif268 directly controls expression of other genes, which makes this protein an important object of studies aimed at understanding the orchestration of neuronal responses to a variety of stimuli. In addition, mice with genetic ablation of the gene have recently become available, which provides novel tools to complement previous studies on gene and protein expression patterns.

In this review, we will present the results of the studies that have documented plasticity-related expression of zif268 in the mammalian brain, with a special emphasis on long-term potentiation and behavioral training, in which the evidence for plasticity-linked function of this gene appears to be particularly strong. We have collected the data on patterns of the expression of zif268 in the brain under different conditions of behavioral, electrophysiological and pharmacological stimulation in a hope that such a synthesis of information may offer clues to its possible physiological function, which still remains elusive. We also consider the recent data on zif268 products’ expression and function in cortical plasticity. For an extensive coverage of the previous literature, the reader is referred to the earlier reviews (Kaczmarek and Chaudhuri, 1997, Tischmeyer and Grimm, 1999, Clayton, 2000, Guzowski, 2002, Leah and Wilce, 2002, Davis et al., 2003, Bozon et al., 2003). It is also worth mentioning that much elaborated cause for a role of this gene has been made in the avian brain in the context of song learning. This issue has been excellently covered by Mello's recent review (Mello, 2002). In this section, we shall discuss the most general features of the gene, the protein structure, and regulation as well as expression pattern in the naive brain, which will allow a better understanding of the relation between zif268 expression and neuronal plasticity. A detailed discussion of the complicated mechanisms controlling zif268 expression, many possible interactions between Zif268 and other transcription factors and, finally, a variety of different late-response genes whose expression could be regulated by Zif268 allows us to consider various potential functions of Zif268.

Section snippets

Characteristics of zif268 and its protein

Following the original observation of zif268 as NGF-inducible and thus possibly related to neuronal functions (Milbrandt, 1987), it was noted that this response could also be triggered by either neurotransmitters or depolarization, which suggested a potential function of Zif268 in the mature nervous system (Christy et al., 1988, Lemaire et al., 1988, Sukhatme et al., 1988, Arenander et al., 1989, Ito et al., 1990). A more convincing argument was given by Sukhatme et al. (1988), who confirmed

Learning-related gene expression

Keeping in mind complex mechanisms controlling zif268 expression, many possible interactions between Zif268 and other transcription factors, a variety of different late-response genes whose expression could be regulated by Zif268, and the time-course of its expression, we can consider various potential functions of Zif268. In this section, we would like to present possible functions of regulatory genes in general, which will allow us to discuss the specific role of Zif268 in the neuronal cell

Basal expression of zif268 mRNA and protein in the brain

In the brain, Zif268 has a distinct basal expression, i.e., the one maintained by normal ongoing synaptic or neurohormonal/neurotrophic activity (Worley et al., 1991, Herdegen and Leah, 1998, Beckmann and Wilce, 1997). This feature is probably vital for Zif268 functions since it allows for either increasing or decreasing the level of its expression.

High basal levels of zif268 and its protein have repeatedly been observed in the visual cortex of various mammalian species (for details, see

Stress and expression of zif268

Stress appears to be an indissociable component of learning processes and therefore it is very important to keep in mind that zif268 expression may at least partly result from stressful aspects of learning situation. On the other hand, all the stress experiments described below involve also aversive learning (context conditioning) of the stressful situation. Thus, they are not fundamentally different from, e.g., classical fear conditioning.

Schreiber et al. (1991b) observed an induction of zif268

Visual cortex

The expression of zif268 products in neurons is maintained at a relatively high level by ongoing synaptic stimulation. However, numerous physiological and pharmacological stimuli can induce a rapid up-regulation of Zif268 in specific areas of the brain. On the other hand, the level of Zif268 expression can be markedly decreased after sensory deprivation. The expression patterns of zif268 and its protein in the visual cortex in response to changing visual conditions have been extensively covered

Seizure-induced expression of zif268 products in the hippocampus

Both zif268 mRNA and its protein expressions have been demonstrated to be induced in the hippocampus in response to a variety of seizure-inducing stimuli. Saffen et al. (1988), as well as Yount et al. (1994), noted that the administration of the convulsant pentylenetetrazole (aka Metrazole) caused a rapid and transient increase of zif268 in the rat hippocampus. Moreover, both single and repeated electrically induced seizures evoked an increase in zif268 mRNA expression, which was most prominent

zif268 products in long-term potentiation

The term long-term potentiation (LTP) refers to the phenomenon of the activity-dependent increase in synaptic efficacy, which serves as an important model for the mechanisms responsible for modification of the responses in the brain evoked by experience. There are several forms of LTP which differ as far as their location, stimulation paradigms and the pharmacological properties are concerned (see Bliss and Collingridge, 1993). The original description involved awake rabbits in which the

Two-way avoidance training

The first demonstration of the increased level of zif268 mRNA resulting from behavioral training was provided by Nikolaev et al. (1992) with the use of the training of the two-way avoidance reaction. The two-way (active) avoidance behavior is acquired in a shuttle-box apparatus, which consists of two compartments. Both of them are equipped with a source of a conditioned stimulus (CS) and a gridded floor through which an unconditioned stimulus (US, a footshock) can be delivered. The animal is

Summary

Struhl (1991) estimated that there are at least hundreds of regulatory transcription factors. These transcription factors (TFs) could potentially regulate an enormous number of different late-response genes. One of these TFs is Zif268, whose expression has been described in many pharmacological, behavioral and electrophysiological paradigms. However, the physiological role of its protein in the neuron still remains elusive.

Most of our present knowledge regarding zif268 induction is based on

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