MSK1 regulates transcriptional induction of Arc/Arg3.1 in response to neurotrophins

Abstract

The immediate early gene activity‐regulated cytoskeletal protein (Arc)/Arg3.1 and the neurotrophin brain‐derived neurotrophic factor (BDNF) play important roles in synaptic plasticity and learning and memory in the mammalian brain. However, the mechanisms by which BDNF regulates the expression of Arc/Arg3.1 are unclear. In this study, we show that BDNF acts via the ERK1/2 pathway to activate the nuclear kinase mitogen‐ and stress‐activated protein kinase 1 (MSK1). MSK1 then induces Arc/Arg3.1 expression via the phosphorylation of histone H3 at the Arc/Arg3.1 promoter. MSK1 can also phosphorylate the transcription factor cyclic‐AMP response element‐binding protein (CREB) on Ser133. However, this is not required for BDNF‐induced Arc.Arg3.1 transcription as a Ser133Ala knockin mutation had no effect on Arc/Arg3.1 induction. In parallel, ERK1/2 directly activates Arc/Arg3.1 mRNA transcription via at least one serum response element on the promoter, which bind a complex of the Serum Response Factor (SRF) and a Ternary Complex Factor (TCF).

Involvement of SRF coactivator MKL2 in BDNF‐mediated activation of the synaptic activity‐responsive element in the Arc gene

“…A recent study has demonstrated that BDNF‐mediated Arc gene expression is controlled by MSK1 (Hunter et al . ). Hunter et al .…”

“…Hunter et al . () also discussed the possible involvement of Elk1, a TCF family member, in BDNF‐mediated Arc gene expression, because of the direct activation of Arc mRNA transcription by ERK1/2. However, direct evidence of Elk1 involvement in Arc gene expression was not shown in the study by Hunter et al .…”

“…A recent study has demonstrated that BDNF-mediated Arc gene expression is controlled by MSK1 (Hunter et al 2017). Hunter et al (2017) also discussed the possible involvement of Elk1, a TCF family member, in BDNF-mediated Arc gene expression, because of the direct activation of Arc mRNA transcription by ERK1/2. However, direct evidence of Elk1 involvement in Arc gene expression was not shown in the study by Hunter et al Therefore, we constructed FLAGtagged Elk1 for use in a luciferase assay.…”

Enhancing cognition through pharmacological and environmental interventions: Examples from preclinical models of neurodevelopmental disorders

“…This idea is borne out for a model of non-syndromic ID, the Gdi1-null mouse, which did not show the expected cognitive impairment when housed in mildly enriched environments but only when housing was a mildly impoverished environment (Bianchi et al, 2009;D'Adamo et al, 2014;De Giorgio, 2017). This may be explained by the neurobiology of the Gdi1-null mutant that curtails the benefit it can get from environmental enrichment, in spite of an increased number of dendritic spines this environment elicits in the brain (Correa et al, 2012;Daumas et al, 2017;Hunter et al, 2017): In Gdi1-null mice the presynaptic recycling of glutamatergic vesicles remains time-limited, hence the beneficial effects of enrichment remain curtailed and ineffective on some sustained tasks (Bianchi et al, 2009;D'Adamo et al, 2014;Ezaki and Nakakihara, 2012;More et al, 2017;Strobl-Wildemann et al, 2011). Finally, it is important to note that the proposed outcomes of this model also would be influenced by the age at which enrichment began, and the duration of exposure.…”

“…MSK1 has been identified as a link between cellsurface neurotransmitter receptors and the gene expression necessary for long-term memory (Choi et al, 2017;Karelina et al, 2012;Karelina et al, 2015). MSK1 exerts its physiological effects by coupling the activation of BDNF receptors to the regulation of transcription via the phosphorylation of CREB (Daumas et al, 2017;Hunter et al, 2017), and due to its position within the nucleus, could be a more precise target for a putative nootropic. MSK1's role is central for homeostasis in response to environmental changes and is highly involved in environmental-induced synaptic transmission effects via its action on immediate early gene activityregulated cytoskeletal protein Arc/Arg3.1 (Correa et al, 2012;Daumas et al, 2017;Hunter et al, 2017).…”