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

Chris J Hunter,J Simon C Arthur,Kathleen M S E Reyskens,Rachel Toth,Bruno G Frenguelli,Lucia Privitera,Sonia A Correa,Judit Remenyi,Kirsty J Martin

doi:10.1002/2211-5463.12232

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).

Highlights

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
The induction of Arc/Arg3.1 mRNA following BDNF stimulation was not blocked by the PI3 kinase inhibitor PI103, the p38 inhibitor SB203580 or the CaMK inhibitor Kn-93 (Fig. 1A) at concentrations previously established to inhibit the relevant kinases in cells [41]
Double knockout of mitogen- and stressactivated protein kinase 1 (MSK1) and 2 (MSK1/2 KO) greatly reduced the initial induction of Arc/Arg3.1 mRNA by BDNF at 1 h, the knockout had less effect at 3, 6 and 8 h, where the induction of Arc/Arg3.1 was no different between wild-type and MSK1/2 KO mice (Fig. 1B)

Summary

Introduction

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. MSK1 can phosphorylate the transcription factor cyclic-AMP response element-binding protein (CREB) on Ser133. This is not required for BDNF-induced Arc.Arg3.1 transcription as a Ser133Ala knockin mutation had no effect on Arc/Arg3.1 induction. CREs are bound by cyclic-AMP response element-binding protein (CREB), or the related transcription factors ATF1 or CREM. Abbreviations Arc, activity-regulated cytoskeletal protein; BDNF, brain-derived neurotrophic factor; CREB, cyclic-AMP response element-binding protein; CRE, cyclic-AMP response elements; MSK1, mitogen- and stress-activated protein kinase 1; NMDA, N-Methyl-D-aspartic acid; SRE, serum response element.

Methods

Results

Conclusion