Figure 2.

Model for EGR1 regulations and functions in the central nervous system in the context of synaptic plasticity. In response to various stimuli such as stress or learning tasks triggering growth factors release, hormones secretion, or neuronal activity, several intracellular signaling pathway including mitogen-activated protein kinases (MAPK) or AKT are activated. Transcription factors such as serum response factor (SRF), cyclic AMP-response element binding protein (CREB), or Ets-like-1 (ELK1), are thus induced and rapidly regulate Egr1 transcription. EGR1 can in turn directly regulate a wide array of transcriptional targets related to multiple biological functions related to synaptic plasticity: vesicular release and endocytosis, neurotransmitters metabolism, micro-RNA (miRNA), receptors, signaling pathways, actin cytoskeleton, as well as component of the proteasome complex. A few validated EGR1 targets are depicted under each biological functions. Through such a wide array of direct transcriptional targets, EGR1 can thus regulate multiple aspects of synaptic plasticity, and thus orchestrate the integration of environmental stimuli at the synaptic plasticity level to modulate relevant high order processes such as learning and memory, addiction, anxiety, and neuropsychiatric disorders. Finally, several negative feedback mechanisms are also engaged, either directly through EGR1 itself, or indirectly through its direct targets such as NAB1 or miR-124. Arc, activity-regulated cytoskeleton-associated protein; Chrna7, cholinergic receptor nicotinic alpha 7 subunit; ERK1/2, extracellular signal-regulated kinase (ERK)s 1/2; Gad1, glutamate decarboxylase 1; Gr, Glucocorticoids receptor; Grin1, glutamate ionotropic receptor N-methyl-D-aspartate (NMDA) type subunit 1, JNK, Jun N-terminal kinase; Mapk1, mitogen activated protein kinase 1; NAB1, NGFI-A-1; PSD-95, Postsynaptic density protein 95; Snap29, synaptosomal-associated protein 29; Snap91, synaptosomal-associated protein 91; Stx6, syntaxin 6.