Activating transcription factor 3 and the nervous system

Abstract

Activating transcription factor 3 (ATF3) belongs to the ATF/cyclic AMP responsive element binding family of transcription factors and is often described as an adaptive response gene whose activity is usually regulated by stressful stimuli. Although expressed in a number of splice variants and generally recognized as a transcriptional repressor, ATF3 has the ability to interact with a number of other transcription factors including c-Jun to form complexes which not only repress, but can also activate various genes. ATF3 expression is modulated mainly at the transcriptional level and has markedly different effects in different types of cell. The levels of ATF3 mRNA and protein are normally very low in neurons and glia but their expression is rapidly upregulated in response to injury. ATF3 expression in neurons is closely linked to their survival and the regeneration of their axons following axotomy, and that in peripheral nerves correlates with the generation of a Schwann cell phenotype that is conducive to axonal regeneration. ATF3 is also induced by Toll-like receptor (TLR) ligands but acts as a negative regulator of TLR signaling, suppressing the innate immune response which is involved in immuno-surveillance and can enhance or reduce the survival of injured neurons and promote the regeneration of their axons.

Keywords: ATF3; c-Jun.

Figure 1

Activating transcription factor 3 (ATF3) is expressed in axotomized, regeneration-competent neurons. (A) ATF3 (green) is concentrated in the nucleus of a lumbar motor neuron (arrowed) from an adult rat 14 days following sciatic nerve transaction. This type of cell regenerates its axon vigorously following nerve injury. Neurofilament immunoreactivity (red) has been used to show neuronal cytoplasm. The scale bar also applies to (D). (B) ATF3 (green) is present in the nuclei of preganglionic parasympathetic neurons in the dorsal nucleus of the vagus (outlined with a dashed line) and in motor neurons of the hypoglossal nucleus (asterisk) 5 days after crush injury to the vagus and hypoglossal nerves in an adult rat. These neurons also regenerate axons following injury. CD11b immunoreactivity (red) shows reactive microglia around the axotomized neurons. The scale bar also applies to (C). (C,D) Show the results of an experiment where a peripheral nerve graft was implanted into the cerebellum of an adult rat, axotomizing both deep nucleus neurons and Purkinje cells. Fourteen days after grafting, ATF3 (green) can be seen in the nuclei (arrows) of neurons within a cerebellar deep nucleus in (D) but not in the nuclei of Purkinje cells, arrowed in (C). Deep nucleus neurons regenerate axons into grafts in the cerebellum but Purkinje cells do not do so; ATF3 is expressed only by the neurons which mount a regenerative response to axotomy. Neurofilament and calbindin immunoreactivity (red) has been used to identify Purkinje cells.

Figure 2

Activating transcription factor 3 (ATF3) gene and protein structure. (A) A schematic representation of ATF3 gene structure and transcript splice variants. The human ATF3 gene spans approximately 56 kb on chromosome 1q32.3, and comprises six exons. This schematic adopts the exon nomenclature used by other research groups (Hashimoto et al., ; Pan et al., ; Hartman et al., 2004). The start codon, denoted by the letter “s,” is located within exon B. The respective in-frame stop codons are denoted by “*” within each transcript. Note that the two transcripts which give rise to full-length ATF3 use different promoters, P1 and P2, and vary only in their 5′ untranslated region owing to the incorporation of exon A-1 or A, respectively. P1 is non-canonical, lying some ~43.5 kb upstream of P2, and was only recently described (Miyazaki et al., 2009). Note that exons B1 and B2 in ATF3ΔZip2c are not the same as those annotated B1 and B2 in ATF3b; the respective spliced fragments of exon B are of different sizes and use different splice donor and acceptor sites. Exons are not shown to scale. (B) The predicted protein structure for each of the ATF3 mRNAs is shown in (A), with the activation, repression, basic, and leucine zipper regions designated. Modified from Pan et al. (2003). aa, Amino acids.

Figure 3

Diagram showing the induction of ATF3 in a neuron by different stimuli and its effect on some targets relevant to axonal regeneration. The pathways inducing ATF3 expression include axotomy, receptor protein tyrosine kinase stimulation, synaptic NMDA receptor activation and endoplasmic reticulum stress. ATF3 is shown repressing its own expression and that of inflammatory cytokines (IC) and, with other AP-1 factors, activating transcription of c-Jun, SPRR1A, and hsp27.