Elsevier

Brain Research Reviews

Volume 28, Issue 3, December 1998, Pages 370-490
Brain Research Reviews

Full-length review
Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins

https://doi.org/10.1016/S0165-0173(98)00018-6Get rights and content

Abstract

This article reviews findings up to the end of 1997 about the inducible transcription factors (ITFs) c-Jun, JunB, JunD, c-Fos, FosB, Fra-1, Fra-2, Krox-20 (Egr-2) and Krox-24 (NGFI-A, Egr-1, Zif268); and the constitutive transcription factors (CTFs) CREB, CREM, ATF-2 and SRF as they pertain to gene expression in the mammalian nervous system. In the first part we consider basic facts about the expression and activity of these transcription factors: the organization of the encoding genes and their promoters, the second messenger cascades converging on their regulatory promoter sites, the control of their transcription, the binding to dimeric partners and to specific DNA sequences, their trans-activation potential, and their posttranslational modifications. In the second part we describe the expression and possible roles of these transcription factors in neural tissue: in the quiescent brain, during pre- and postnatal development, following sensory stimulation, nerve transection (axotomy), neurodegeneration and apoptosis, hypoxia–ischemia, generalized and limbic seizures, long-term potentiation and learning, drug dependence and withdrawal, and following stimulation by neurotransmitters, hormones and neurotrophins. We also describe their expression and possible roles in glial cells. Finally, we discuss the relevance of their expression for nervous system functioning under normal and patho-physiological conditions.

Introduction

This review has several aims. It summarizes the large amount of information now available about the expression and specific functions of individual transcription factor proteins, in a manner useful to new researchers in the field. Since growing numbers of clinically and physiologically orientated investigators are studying the effects of intentional stimulation on gene expression, this article compiles the basics of ITF and CTF functions, i.e., the controls on expression of their genes, and the range of operations of their proteins. Researchers studying molecular genetic activity with in vitro and cell culture techniques should be confronted with the characteristics of CTF and ITF expressions in the real mammalian brain that are often surprisingly different to those in vitro, and their neglect in advancing their in vitro findings to the in vivo situation. We do not refer to all articles reporting the characteristics and functioning of ITFs and CTFs in the nervous system; our interest is principally in those papers from which general characteristics can be derived. Of all the ITFs, c-Fos has been studied the most and previous reviews have concentrated on it. Here we discuss only a minor, but nevertheless comprehensive subset of publications on c-Fos, and review it as an equal with other ITFs.

Stimulation of neurons can activate two different mechanisms by which they process and transmit the information: the electrophysiological activity that immediately processes and conveys information about the stimulus; and the longer-acting second messenger signal cascades that evoke production of transcription factor proteins which initiate transcription and/or repression of other genes, thereby altering the neurons' responses to subsequent stimuli. The genes activated by transcription factors might be, e.g., new (or more) proteins such as those forming transmitter receptors, ion channels, and cytoskeletal structures; as well as those required for neurotransmitter synthesis and regeneration.

The study of transcription factors in the nervous system is at a relatively early stage but, conversely and importantly, much of what is known about them comes from studying their activities in neural tissue. The importance of transcription factors for living organisms has been deduced principally from in vitro experiments. Recently, however, it has become clear that transcription factors play crucial and specific roles in normal nervous system development and functioning; as well as in the adaptive responses of the nervous system to many different types of stimuli, and to pathological situations. Examples are the control of myelination of peripheral nerve fibers by Krox-20 [1270], degeneration of hypophyseal neurons following the loss of phosphorylation of CREB [1230], deficits in memory formation as the result of partial knock-out of the CREB gene [136], the relationship of c-Fos to developmental apoptosis [1206], the bipartite role of c-Jun as `killer' protein for embryonic neurons in vitro 349, 477, 1149 and as a `rescue' factor in axotomized but regenerating retinal ganglion cells in vivo [1142], the role of Krox-20 and Krox-24 expression in the stabilization of LTP [11], and synchronization of the endogenous circadian rhythm with the environmental zeitgeber via c-Fos and JunB expression [1372]. Investigation of the induction, expression and function of transcription factors has become necessary not only for understanding how gene expression causes long-term changes in nervous system functioning; but also for understanding the role of second messenger systems that are activated within minutes of stimulation, a time frame dominated by classical electrophysiology.

Section snippets

Definitions and the initiation of gene expression

Transcription factors are proteins that control the expression of genes, and as such they are the master regulators of every cell's development and functioning. This functioning depends upon many factors. It is influenced by the circumstances and general activity in the nucleus, and the spatial organization and availability of DNA binding sites [1173]. Individual transcription factor proteins associate with others prior to binding to DNA, often via the string of exposed leucine residues they

Inducible transcription factors (ITFs)

Here we summarize information about the induction, expression and operation of the Jun, Fos and Krox families of inducible transcription factors that is likely to be important to neuroscientists. Such a summary in not available in any other article. More didactic analyses, and details about their molecular biology can be found in other reviews 142, 258, 526, 537, 660, 760, 909, 911, 982, 1055, 1056, 1321.

Constitutive transcription factors (CTFs)

CREB, ATF and SRF proteins are representatives of a class of ubiquitous and continually expressed transcription factors. They are assumed to be constitutively expressed, i.e., their expression is driven by `stand alone' mechanisms within cells and is not dependent upon extracellular signals. With respect to ITFs, the CTFs have three principal actions: (i) they activate or repress the induction of genes encoding ITFs, (ii) they can form activating or repressive heterodimers with ITFs, (ii) they

ITF and CTF expression during nervous system development

Probably more than one half of the genes expressed during development of the nervous system encode transcription factors [491]. These activate or repress particular genes, or activate more transcription factors to initiate cascades of these proteins that regulate cellular replication and differentiation in a precise temporo-spatial order. Information about the homeobox transcription factors in neural development is rapidly accruing, but less is known about the roles of ITF and CTF proteins.

Basal expression in the adult nervous system

In many regions of the adult nervous system there is a constant expression of ITFs, particularly in sensory systems where neurons receive ongoing synaptic input. A detailed description of these basal expressions can be compiled from studies of ITF expressions in the control animals used in many experiments. Also, several studies have specifically addressed basal expressions 509, 663, 664, and recently those of the Jun proteins have been reviewed [483].

The somatosensory system

Tactile stimulation of sensory nerve endings produces some ITF expression in the CNS, but stimulation of nociceptive C-fibers causes a much stronger expression. This is considered separately in Section 8.

In the rat, stimulation of hindlimb nerve Aβ fibers evokes a weak expression of c-Fos and other AP-1 proteins in spinal neurons 510, 584, 894, and tactile stimulation causes a weak expression of ITFs in the somatosensory cortex [675]. Stimulation of vibrissae causes a weak c-Fos expression, and

Noxious stimulation and ITF expression

The discovery of c-Fos in the central nervous system after peripheral noxious stimulation [584] has to be estimated as a hallmark in neuroscience. Since this time, the expression of c-Fos protein has been used for mapping nociceptive pathways, and for examining factors that modulate their activity. Noxious stimulus-induced c-Fos expression has received much attention because noxious stimuli can cause marked and long-term changes in neuronal chemistry and electrophysiology that are thought to be

A selective and lasting expression of c-Jun and JunD in axotomized neurons

The first reports about the unique expression pattern of c-Jun without c-Fos in axotomized neurons appeared in 1989 763, 764 and were consolidated in 1991 503, 625, 765. Transection of nerve fibers (axotomy) provokes a complex reaction in the damaged, i.e., axotomized, neurons, the so-called cell body-response (CBR) 442, 789, 1272, 1273. The CBR depends on de novo protein synthesis 1272, 1273 and comprises intricate changes in gene expression, metabolism and morphology that can differ between

Programmed cell death and neurodegeneration

Hypoxia–ischemia, generalized seizures, removal of target cells, deprivation of growth factors, ageing, morphogenesis and axotomy can all result in a delayed death of neurons that has some of the characteristics of programmed cell death (PCD) 363, 825, 1033; defined by nuclear and DNA fragmentation, chromatin condensation, and cytoplasmic blebbing 300, 397, 887, 1030, 1130. Neither DNA damage nor arrest of protein synthesis per se initiate PCD [1030]. Forskolin and cAMP, but not phorbol ester

Hypoxia–ischemia and seizure

Hypoxia–ischemia (H) and generalized epileptic seizures (GS) are potent inducers of numerous genes encoding immediate regulatory and late effector proteins.They also evoke morphological alterations in the damaged neural tissue and, most importantly, cause (programmed) cell death in vulnerable neurons. The rapid and persisting expression of Jun, Fos and Krox proteins might be a central part of these genetic and subsequent structural changes. Intense transynaptic stimulation of neurons and

Learning, memory and long-term potentiation

There is increasing evidence that both constitutive and inducible transcription factors mediate the long-term alterations in gene activity necessary for conditioning, imprinting, learning and memory 378, 646, 1087.

Drug tolerance and dependence

Transcription factors are certain to have a crucial role in the development of tolerance and dependence, and the mechanisms involved are likely to be similar to those operating in other instances of neural plasticity, such as learning and the development of chronic pain [939]. Here we review alterations in transcription factor levels following acute and chronic drug administration, and following withdrawal from the dependence-inducing drugs cocaine, antidepressants, morphine and ethanol.

Transcription factors in glial cells

Transcription factor activity in glial cells is important because many compounds acting on neurons, or released by them can elicit ITF expression in glia. This would coordinate long-term neuronal and glial responses to a common stimulus, or allow neurons to modify glial genetics in relation to their own activity.

Temporal characteristics of ITF expression

An important characteristic of ITFs is their fast on/off kinetics, but they can also show delayed and prolonged expressions. The extreme cases are the very rapid synthesis of krox-24 (mRNA within 5 min) and the short expression of its protein following synaptic stimulation (half-life 0.5 to 1 h), the delayed (24 to 36 h) but prolonged (over several months) expression of c-Jun following axotomy, and the year-long expression of c-Fos after a single seizure [114].

ITF expressions caused by neurotransmitters and their analogues

Here we examine principally the excitatory amino acids, particularly NMDA because it has a crucial role in ITF expressions caused by other neuroactive compounds; and dopamine because it has been well studied and illustrates interactions between receptor types in induction of ITF expression.

Hormones, neuropeptides and neurotrophins

Unlike synaptically released compounds, hormones entering the CNS can simultaneously affect the functioning of many groups of neurons and/or glia, and coordinate gene expression amongst them. They can induce ITF expressions acutely, as well as modulating expressions caused by other acute stimuli. Hormones also initiate behaviours so that behaviours driven by gene expression can be examined.

Target genes of AP-1 proteins

The Jun and Fos proteins form a particular group of transcription factors because only they bind to the AP-1 sequence with a high affinity, and the binding of non-AP-1 proteins such as ATF-2 to this DNA sequence is strictly dependent upon their forming dimers with the AP-1 proteins. Other AP-1 proteins such as JunB can bind with different proteins to CRE sites and rapidly effect transcription. AP-1 proteins are thus transcriptional enhancers that increase gene expression above basal levels. In

The complexity of transcription factor functioning

The functions a particular inducible transcription factor cannot be simply defined by the genes whose expressions it regulates. A particular ITF may participate in regulating a gene in one circumstance, but regulate other genes in other circumstances. For example, the Fos evoked in spinal neurons by transmitters released from stimulated sensory nerves does not cause expression of prodynorphin, but Fos induced in spinal neurons by serotonin, which is released from descending inputs, does

Perspectives

One has to admit that much of the past and present work on ITF functioning is still at a descriptive level. The elucidation of ITF functions in vivo remains limited by the genetic and biochemical manipulations that can be made with the adult nervous system. In addition, findings from non-neuronal cells, and from cultured embryonic cells can only with utmost caution be translated to the adult brain. Nevertheless, the study of ITFs has generated a new field in neurobiology, as is demonstrated by

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