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Involvement of SRF coactivator MKL 2 in BDNF ‐mediated activation of the synaptic activity‐responsive element in the Arc gene
Author(s) -
Kikuchi Keietsu,
Ihara Daisuke,
Fukuchi Mamoru,
Tanabe Hiroki,
Ishibashi Yuta,
Tsujii Junya,
Tsuda Masaaki,
Kaneda Marisa,
Sakagami Hiroyuki,
Okuno Hiroyuki,
Bito Haruhiko,
Yamazaki Yuya,
Ishikawa Mitsuru,
Tabuchi Akiko
Publication year - 2019
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14596
Subject(s) - serum response factor , coactivator , transcription factor , chromatin immunoprecipitation , arc (geometry) , biology , enhancer , response element , microbiology and biotechnology , immediate early gene , neurotrophic factors , gene knockdown , promoter , gene expression , gene , genetics , receptor , geometry , mathematics
The expression of immediate early genes ( IEG s) is thought to be an essential molecular basis of neuronal plasticity for higher brain function. Many IEG s contain serum response element in their transcriptional regulatory regions and their expression is controlled by serum response factor ( SRF ). SRF is known to play a role in concert with transcriptional cofactors. However, little is known about how SRF cofactors regulate IEG expression during the process of neuronal plasticity. We hypothesized that one of the SRF ‐regulated neuronal IEG s, activity‐regulated cytoskeleton‐associated protein ( Arc ; also termed Arg3.1 ), is regulated by an SRF coactivator, megakaryoblastic leukemia ( MKL ). To test this hypothesis, we initially investigated which binding site of the transcription factor or SRF cofactor contributes to brain‐derived neurotrophic factor ( BDNF )‐induced Arc gene transcription in cultured cortical neurons using transfection and reporter assays. We found that BDNF caused robust induction of Arc gene transcription through a cAMP response element, binding site of myocyte enhancer factor 2, and binding site of SRF in an Arc enhancer, the synaptic activity‐responsive element ( SARE ). Regardless of the requirement for the SRF ‐binding site, the binding site of a ternary complex factor, another SRF cofactor, did not affect BDNF ‐mediated Arc gene transcription. In contrast, chromatin immunoprecipitation revealed occupation of MKL at the SARE . Furthermore, knockdown of MKL 2, but not MKL 1, significantly decreased BDNF ‐mediated activation of the SARE . Taken together, these findings suggest a novel mechanism by which MKL 2 controls the Arc SARE in response to BDNF stimulation.