The regulation and function of c-fos and other immediate early genes in the nervous system

Morgan Sheng and Michael E. Greenberg Department of Microbiology and Molecular Genetics Harvard Medical School Boston. Massachusetts 02115 Introduction The unique morphological and excitable properties of nerve cells endow them with specialized properties that permit the reception, transmission, and storage of information. It has long been recognized that trans- synaptic signals cause rapid responses in neurons. These occur over a time frame ranging from millise- conds (e.g., opening of ligand-gated channels) to sec- onds and minutes (e.g., second messenger-mediated events). Recent studies, however, have revealed that trans.synaptic activation also elicits slower, long-term responses in neural cells that are correlated with, and in some cases shown to be dependent on, the induc- tion of new programs of gene expression (reviewed in Goelet et al., 1986; Black et al., 1987; Comb et al., 1987; Morgan and Curran, 1988). Neuronal gene ex- pression can be modulated by neurotransmitters, mem- brane electrical activity, and neurotrophic growth fac- tors and is likely to play an important role both in the development and in the adaptive plasticity of the ner- vous system. Many of the long-term consequences of trans-synaptic stimulation may therefore be mediated by changes in gene expression. These include altera- tions in neuronal sprouting or synaptic density and changes in the level of expression of neurotransmit- ters, receptors, and ion channel proteins. In inver- tebrates, the activation of new gene expression in neurons has been shown to be critical for the devel- opment of a learning-related long-term facilitation (Montarolo et al., 1986). Substantial progress has been made over the last 5 years in identifying the genes that are responsive to trans-synaptic stimulation and membrane electrical activity in neural cells. These genes fall into two gen- eral classes: genes whose transcription is activated rapidly and transiently within minutes of stimulation (Greenberg et al., 1985; Morgan and Curran, 1986; Bartel et al., 1989; Barzilai et al., 1989), termed the cel- lular immediate early genes (IEGs), and the late re- sponse genes (Merlie et al., 1984; Castellucci et al., 1988; Goldman et al., 1988; Barzilai et al., 1989; Offord and Catterall, 1989; Klarsfeld et al., 1989), whose ex- pression is induced (or repressed) more slowly, over a time frame of hours, via a mechanism that is gener- ally dependent on new protein synthesis. While the distinction between the IECs and the late response genes is not always clear-cut, it has been proposed that IEGs encode regulatory proteins that control the expression of late response genes. The products of the late response genes are then thought to serve more specific effector functions in the neuronal re- sponse. Recent studies, which are the subject of this review, have provided increasing support for this idea. Many IEGs have been shown to encode transcription factors. By directing specific programs of late gene ex- pression, the induction of these proteins could there- fore mediate many of the long-term responses of the neuron to trans-synaptic signals. What Are Immediate Early Genes? The activation of IECs by extracellular stimuli is not specific to neuronal cells. The IEGs were first charac- terized in nonneuronal cells through efforts to iden- tify growth factor-responsive genes that might con- trol the reentry of Go resting cells into cell cycle. This work resulted in the discovery of a class genes whose transcription is activated within minutes after addition of a growth factor. The c-fos and c-myc proto- oncogenes were among the first IECs to be identified (Kelly et 1983; Greenberg and Ziff, 1984) are prototypic members of this family. c-fos transcription- al activation occurs within a few minutes of growth factor stimulation and precedes the activation of c-myc (Greenberg and Ziff, 1984; Kruijer et al., Muller et al., 1984). The induction of these genes is transient; the level of c-fos transcription is once again undetect- able 30 min after growth factor treatment. The obser- vation that growth factors activate the transcription of two genes whose mutation or deregulated expression can lead to cell transformation suggested that Fos and Myc proteins could have important regulatory func- tions during cell proliferation. Indeed, studies using c-fos anti-sense RNA or anti-c-fos antibodies indicate that the activation of c-fos is critical for reentry of qui- escent fibroblasts into the cell cycle (Nishikura and Murray, 1987; Riabowol et al., 1988). In addition to c-fos and c-myc, a large number of other IEGs have been identified by the differential screening of cDNA libraries from growth factor-stimulated cells (Coch- ran et al., 1983; Lau and Nathans, 1985, 1987; Almen- dral et al., 1988; Lim 1987; Kujubu 1987). The total number of IECs is now thought to be close to 100, though relatively few of these genes have been extensively characterized. In general, IEGs share the following characteristics: their expression is low or undetectable in quiescent cells, but is rapidly induced at the transcriptional level within minutes of extracellular stimulation; this tran- scriptional induction is transient and independent of new protein synthesis; the subsequent shut-off of transcription requires new protein synthesis; the mRNAs transcribed from these genes often have a very short half-life (in the case of c-fos, approximately