Elsevier

Neurochemistry International

Volume 33, Issue 4, 1 October 1998, Pages 287-297
Neurochemistry International

Invited review c-Fos as a transcription factor: a stressful (re)view from a functional map

https://doi.org/10.1016/S0197-0186(98)00023-0Get rights and content

Abstract

This article summarizes the achievements that have been accumulated about the role of c-Fos as a transcription factor and as a functional marker of activated neurons. Since its discovery, more than a decade ago, as an inducible immediate-early gene encoding a transcription factor, or third messenger, involved in stimulus-transcription coupling and mediation of extracellular signals to long-term changes in cellular phenotype, c-fos became the most widely used powerful tool to delineate individual neurons as well as extended circuitries that are responsive to wide variety of external stimuli. There still remain uncertainties as to how general is the c-fos induction in the central neurons, and whether the threshold of c-fos induction is comparable along a certain neuronal circuit. The major limitation of this technology is that c-fos does not mark cells with a net inhibitory synaptic or transcriptional drive, and c-fos induction, as a generic marker of trans-synaptic activation, does not provide evidence for transcriptional activation of specific target genes in a certain cell type of interest. The first part of the review focuses on recent functional data on c-fos as transcription factor, while the second part discusses c-fos as a cellular marker of transcriptional activity in the stress-related circuitry.

Section snippets

Introductioncm

Stereotypic inducibility of c-fos proto-oncogene rendered this cellular immediate-early gene (IEG) to be the most widely used functional anatomical mapping tool to identify cells and extended circuitries that became activated in response to various stimuli (Greenberg and Ziff, 1984;Sagar et al., 1988; Ceccatelli et al., 1989; Bullit, 1990). On the other hand, c-fos (and other members of its family) by dimerization with that of the members of the jun family, forms a transcription factor referred

c-fos and their relatives

To date four major protein members of the Fos family have been identified: c-Fos, FosB, Fra-1 and Fra-2. (Greenberg and Ziff, 1984; Zerial et al.; 1989; Cohen and Curran, 1988; Nishina et al.; 1990) (see Table 1). These proteins are encoded by genes containing four exons and three introns (van Straaten et al., 1983) and possess a leucin zipper motif that promotes heterodimerization with that of the members of the Jun family (c-jun, JunB and JunD) to form a transcription factor referred to as

c-fos induction in the paraventricular nucleus

One of the best output of the c-fos strategy is the functional anatomical mapping of neuronal circuits underlying neuronendocrine-, autonomical- and behavioral responses induced by stress. Exogenous and endogenous challenges activate the parvocellular neurosecretory neurons in the hypothalamic paraventricular nucleus to initiate stress cascade by delivering the two main corticotropin releasing factors, CRF-41 and arginine vasopressin into the hypophyseal portal circulation (review: see Antoni,

Summary

c-fos-based functional mapping has been validated as a powerful technic to reveal activated neurons and characterize cell groups that may be associated with functional circuits in a situation specific manner, in spite of uncertainties the exact functional roles of c-Fos, as a transcription factor, in the central nervous system as well as about the signal transduction mechanisms that activate immediate-early gene induction in vivo.

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