Full-length reviewInducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins
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
References (1440)
- et al.
c-fos expresion in rat lumbar spinal cord during the development of adjuvant-induced arthritis
Neuroscience
(1992) - et al.
C-fos expression in rat lumbar spinal cord following peripheral stimulation in adjuvant-induced arthritic and normal rats
Brain Res.
(1993) - et al.
Intense cold noxious stimulation of the rat hindpaw induces c-fos expression in lumbar spinal cord neurons
Neuroscience
(1994) - et al.
Cortical refractoriness to N-methyl-d,l-aspartic acid (NMA) stimulation in the lactating rat: recovery after pup removal and blockade of progesterone receptors
Brain Res.
(1993) - et al.
NMDA and non-NMDA receptor antagonists inhibit photic induction of Fos protein in the hamster suprachiasmatic nucleus
Brain Res. Bull.
(1992) - et al.
Correlations between immediate early gene induction and the persistence of long-term potentiation
Neuroscience
(1993) Diurnal expression of NGF1-A mRNA in retinal degeneration slow (rds) mutant mouse retina
FEBS Lett.
(1994)- et al.
Mirror Pain in the formalin test: behavioral and 2-deoxyglucose studies
Pain
(1993) - et al.
Sex-dependent effects of formalin and restraint on c-Fos expression in the septum and hippocampus of the rat
Neuroscience
(1997) - et al.
Induction of KROX-20 expression after focal cerebral ischemia
Biochem. Biophys. Res. Commun.
(1992)
The kinetics and morphological characteristics of the macrophage–microglial response to kainic acid-induced neuronal degeneration
Neuroscience
Expression of c-fos in restricted areas of the basal forebrain and brainstem following single or combined intraventricular infusions of vasopressin and corticotropin-releasing factor
Neuroscience
The jun protooncogene is positively autoregulated by its product; Jun/AP-1
Cell
Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor
Cell
Selective uptake and degradation of c-Fos and v-Fos by rat liver lysosomes
FEBS Lett.
Effects of early experience on c-fos gene expression in the chick forebrain
Brain Res.
Identification of a TPA-responsive element mediating preferential transactivation of the galanin gene promoter in chromaffin cells
J. Biol. Chem.
E1A-associated p300 and CREB-associated CBP belong to a conserved family of coactivators
Cell
Increased expression and subcellular translocation of the mitogen activated protein kinase kinase and mitogen-activated protein kinase in Alzheimer's disease
Neuroscience
Dopamineric control of gene transcription during striatal ontogeny. c-fos induction by D1-receptor activation in the developing striosomes
Mol. Brain Res.
N-methyl-d-aspartate receptor activation in the neostriatum increases c-fos and fos-related antigens selectively in medium-sized neurons
Neuroscience
Effects of single cyclosporin A pretreatment on pentylenetetrazol-induced convulsion and on TRE-binding activity in the rat brain
Mol. Brain Res.
Repeated D-1 receptor agonist treatment blocks cocaine-induced locomotor activity and c-fos expressed
Brain Res.
Progesterone treatment increases Fos-immunoreactivity within some progestin receptor-containing neurons in localized regions of female rat forebrain
Brain Res.
IP-1: a dominant inhibitor of Fos/Jun whose activity is modulated by phosphorylation
Cell
c-Jun, Krox-24 and c-Fos expression in hippocampal grafts placed in excitotoxic hippocampal lesion of the rat
Exp. Neurol.
Particular nuclear transcription factors responsive to systemic administration of kainic acid in murine brain
Neurochem. Int.
N-methyl-d-aspartate receptors are critical for mediating the effects of glutamate on intracellular calcium concentration and immediate early gene expression in cultured hippocampal neurons
Neuroscience
Fibroblast growth factors: activities and significance of non-neurotrophin neurotrophic growth factors
Curr. Opin. Neurobiol.
Circadian expression of transcription factor Fra-2 in the rat pineal gland
J. Biol. Chem.
Hippocampal damage and kainic acid injection induce a rapid increase in mRNA for BDNF and NGF in the rat brain
Exp. Neurol.
Adrenalectomy attenuates kainic acid-elicited increases of messenger RNAs for neurotrophins and their receptors in the rat brain
Neuroscience
Chronic desipramine alters stress-induced behaviors and regional expression of the immediate early gene, c-fos
Pharmacol. Biochem. Behav.
Immediate early gene expression during morphine withdrawal
Neuropharmacology
ERG transcription factor in the nervous system
Neurochem. Int.
Concurrent immediate early gene induction by epileptic seizures in heterotopic cortical grafts and neocortex
Mol. Brain Res.
NMDA receptors-dependent and -independent immediate early gene expression induced by focal mechanical brain injury
Neurochem. Int.
Functional antagonism between c-Jun and MyoD proteins: a direct physical association
Cell
N-methyl-d-aspartate and non-N-methyl-d-aspartate receptor antagonism reduces Fos-like immunoreactivity in central trigeminal neurons after corneal stimulation in the rat
Neuroscience
Dimerization and DNA binding alter phosphorylation of Fos and Jun
Proc. Natl. Acad. Sci. USA
Redox regulation of Fos and Jun DNA-binding activity in vitro
Science
Activating transcription factor-2 DNA-binding activity is stimulated by phosphorylation catalyzed by p42 and p54 microtubule-associated protein kinase
Mol. Endocrinol.
Target specificity of neuronal RNA-binding protein, Mel-N1 direct binding to the 3′ untranslated region of its own mRNA
Nucleic Acids Res.
The role of immediate early genes in the stabilization of long-term potentiation
Mol. Neurobiol.
Mapping of functional domains in Fos and Jun proteins using epitope-specific antibodies
Oncogene
BDNF enhances the differentiation but not the survival of CNS stem cell-derived neuronal precursors
J. Neurosci.
Protein phosphatase 2A potentiates activity of promoters containing AP-1-binding elements
Mol. Cell. Biol.
Expression of a peptide inhibitor of protein phosphatase 1 increases phosphorylation and activity of CREB in NIH 3T3 fibroblasts
Mol. Cell. Biol.
Developmental regulation of Fos and Fos-related antigens in cerebral cortex, striatum, hippocampus, and cerebellum of the rat
J. Comp. Neurol.
Complexity of the early genetic response to growth factors in mouse fibroblasts
Mol. Cell. Biol.
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