Role of Megakaryoblastic Acute Leukemia-1 in ERK1/2-Dependent Stimulation of Serum Response Factor-Driven Transcription by BDNF or Increased Synaptic Activity

Kalita, Katarzyna; Kharebava, Giorgi; Zheng, Jing-Juan; Hetman, Michał

doi:10.1523/jneurosci.2644-06.2006

Cited by 80 publications

(85 citation statements)

References 55 publications

(85 reference statements)

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“…Recent evidence suggests that BDNF and NGF also activate MKL/SRF transcriptional responses (24,26). Although it is unknown whether BDNF and NGF affect den- dritic morphology in an MKL-dependent manner, it would be interesting to examine whether such neurotrophin signals and activin signals converge on dendritic morphology via a common pathway, such as the cytoplasmic retention of SCAI, or convey distinct information spatiotemporally.…”

Section: Discussionmentioning

confidence: 99%

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Involvement of the Serum Response Factor Coactivator Megakaryoblastic Leukemia (MKL) in the Activin-regulated Dendritic Complexity of Rat Cortical Neurons*

Ishikawa

Nishijima

Shiota

et al. 2010

Journal of Biological Chemistry

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Dynamic changes in neuronal morphology and transcriptional regulation play crucial roles in the neuronal network and function. Accumulating evidence suggests that the megakaryoblastic leukemia (MKL) family members, which function not only as actin-binding proteins but also as serum response factor (SRF) transcriptional coactivators, regulate neuronal morphology. However, the extracellular ligands and signaling pathways, which activate MKL-mediated morphological changes in neurons, remain unresolved. Here, we demonstrate that in addition to MKL1, MKL2, highly enriched in the forebrain, strongly contributes to the dendritic complexity, and this process is triggered by stimulation with activin, a member of the transforming growth factor ␤ (TGF-␤) superfamily. Activin promoted dendritic complexity in a SRF-and MKL-dependent manner without drastically affecting MKL localization and protein levels. In contrast, activin promoted the nuclear export of suppressor of cancer cell invasion (SCAI), which is a corepressor for SRF and MKL. Furthermore, overexpression of SCAI blocked activin-induced SRF transcriptional responses and dendritic complexity. Collectively, these results strongly suggest that activin-SCAI-MKL signaling is a novel pathway that regulates the dendritic morphology of rat cortical neurons by excluding SCAI from the nucleus and activating MKL/SRF-mediated gene expression. Serum response factor (SRF)4 is a transcription factor that binds to a consensus sequence CC(A/T) 6 GG (called the CArG box), which is present in the promoters of several immediateearly or cytoskeletal genes (1). Several studies have demonstrated that deletion mutants of SRF in the mouse brain result in the attenuation of activity-dependent expression of immediate-early genes, impair synaptic plasticity and learning (2, 3), reduce neurite outgrowth, and show abnormality of pathfindings and neuronal migration (4, 5). These findings strongly suggest that SRF plays an important role in neuronal development and plasticity (6). SRF-dependent transcription is controlled by at least two different types of coactivators. One comprises the ternary complex factors, which mainly regulate the immediateearly genes such as c-fos (7). The other type of coactivator comprises megakaryoblastic leukemia (MKL) family members. The MKL family consists of megakaryocytic acute leukemia/ megakaryoblastic leukemia 1/myocardin-related transcription factor-A/basic SAP, and coiled-coil domain (MAL/MKL1/ MRTF-A/BSAC) and MKL2/MRTF-B (8 -13). In nonneuronal cells, MKL1 is primarily activated by actin rearrangement stimulated with the activation of Rho GTPases; that is, release of MKL1 from G-actin enables MKL1 to translocate to the nucleus where it binds to and activates SRF (14). MKL2, in addition to MKL1, regulates a set of cytoskeletal genes (11, 12). Furthermore, suppressor of cancer cell invasion (SCAI) has recently been identified as an MKL-interacting cofactor that inhibits cancer cell invasion (15). Therefore, SRF-driven transcriptional regulation appears to be ...

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Section: Discussionmentioning

confidence: 99%

“…In neurons, MKL1 regulates SRFmediated transcription through the RhoA or brain-derived neurotrophic factor (BDNF)-induced ERK1/2 signaling pathway (23,24). In addition, MKL1 is highly expressed in the forebrain and regulates the neuronal morphology of cortical or hippocampal neurons (5,25).…”

mentioning

confidence: 99%

Involvement of the Serum Response Factor Coactivator Megakaryoblastic Leukemia (MKL) in the Activin-regulated Dendritic Complexity of Rat Cortical Neurons*

Ishikawa

Nishijima

Shiota

et al. 2010

Journal of Biological Chemistry

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“…The following plasmids have been described previously: EF1␣LacZ, 1ϫCRE (CRE-luciferase reporter) (27), a hemagglutinin (HA)-tagged expression vector for constitutively active MKK1 (28), a dominant negative mutant of SRF (DN-SRF) (29,30), dominant negative Flag-MKL1 (C630) (31), a dominant negative mutant of p53 (32), shMKL1 (33), pSUPER-shGFP (where shGFP is a small hairpin RNA [shRNA] targeting green fluorescent protein) (33), a mutant form of CREB (A-CREB) (34),and an expression vector for inducible cAMP early repressor 2␥ (ICER II␥) (35). Small hairpin RNA constructs that were based on the pRNAT-H1.1/Shuttle vector and targeting serum response factor (shSRF) or negative control were donated by B. P. Herring (Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN) (36).…”

Section: Methodsmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor Induces Matrix Metalloproteinase 9 Expression in Neurons via the Serum Response Factor/c-Fos Pathway

Kuzniewska

Rejmak

Malik

et al. 2013

Molecular and Cellular Biology

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bBrain-derived neurotrophic factor (BDNF) plays a pivotal role in the regulation of the transcription of genes that encode proplasticity proteins. In the present study, we provide evidence that stimulation of rat primary cortical neurons with BDNF upregulates matrix metalloproteinase 9 (MMP-9) mRNA and protein levels and increases enzymatic activity. The BDNF-induced MMP-9 transcription was dependent on extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and c-Fos expression. Overexpression of AP-1 dimers in neurons led to MMP-9 promoter activation, with the most potent being those that contained c-Fos, whereas knockdown of endogenous c-Fos by small hairpin RNA (shRNA) reduced BDNF-mediated MMP-9 transcription. Additionally, mutation of the proximal AP-1 binding site in the MMP-9 promoter inhibited the activation of MMP-9 transcription. BDNF stimulation of neurons induced binding of endogenous c-Fos to the proximal MMP-9 promoter region. Furthermore, as the c-Fos gene is a known target of serum response factor (SRF), we investigated whether SRF contributes to MMP-9 transcription. Inhibition of SRF and its cofactors by either overexpression of dominant negative mutants or shRNA decreased MMP-9 promoter activation. In contrast, MMP-9 transcription was not dependent on CREB activity. Finally, we showed that neuronal activity stimulates MMP-9 transcription in a tyrosine kinase receptor B (TrkB)-dependent manner.

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“…Additionally, actin dynamics regulate MAL nuclear translocation (Posern and Treisman, 2006). However in neurons, MAL appears constitutively nuclear (Kalita et al, 2006) (supplemental Fig. 3, available at www.jneurosci.org as supplemental material), arguing for a different mechanism.…”

Section: Actin Modulates Neuronal Morphology By Nuclear Gene Expressionmentioning

confidence: 99%

A Nuclear Actin Function Regulates Neuronal Motility by Serum Response Factor-Dependent Gene Transcription

Stern

Debre²,

Stritt³

et al. 2009

J. Neurosci.

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Neuronal motility relies on actin treadmilling. In addition to regulating cytoskeletal dynamics in the cytoplasm, actin modulates nuclear gene expression. We present a hitherto unappreciated cross talk of actin signaling with gene expression governing neuronal motility. Toward this end, we used a novel approach using mutant actins either favoring (G15S) or inhibiting (R62D) F-actin assembly. Overexpressing these mutant actins in mouse hippocampal neurons not only modulated growth-cone function but also neurite elongation, which was ambiguous by traditional pharmacological interference. G15S actin enhanced neurite outgrowth and filopodia number. In contrast, R62D reduced neurite length and impaired growth-cone filopodia formation. Growth-cone collapse induced by ephrin-As, a family of repulsive axon guidance molecules, is impaired upon R62D expression, resulting in perseverance of ring-shaped F-actin filaments. R62D-induced phenotypes strongly resemble neurons lacking SRF (Serum Response Factor). SRF controls gene transcription of various actin isoforms (e.g., Actb, Acta1) and actin-binding proteins (e.g., Gsn) and is the archetypical transcription factor to study actin interplay with transcription. We show that neuronal motility evoked by these actin mutants requires SRF activity. Further, constitutively active SRF partially rescues R62D-induced phenotypes. Conversely, actin signaling regulates neuronal SRF-mediated gene expression. Notably, a nucleus-resident actin (R62D NLS ) also regulates SRF's transcriptional activity. Moreover, R62D NLS decreases neuronal motility similar to the cytoplasmic R62D actin mutant although R62D NLS has no access to cytoplasmic actin dynamics. Thus, herein we provide first evidence that neuronal motility not only depends on cytoplasmic actin dynamics but also on the availability of actin to modulate nuclear functions such as gene transcription.

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Role of Megakaryoblastic Acute Leukemia-1 in ERK1/2-Dependent Stimulation of Serum Response Factor-Driven Transcription by BDNF or Increased Synaptic Activity

Cited by 80 publications

References 55 publications

Involvement of the Serum Response Factor Coactivator Megakaryoblastic Leukemia (MKL) in the Activin-regulated Dendritic Complexity of Rat Cortical Neurons*

Involvement of the Serum Response Factor Coactivator Megakaryoblastic Leukemia (MKL) in the Activin-regulated Dendritic Complexity of Rat Cortical Neurons*

Brain-Derived Neurotrophic Factor Induces Matrix Metalloproteinase 9 Expression in Neurons via the Serum Response Factor/c-Fos Pathway

A Nuclear Actin Function Regulates Neuronal Motility by Serum Response Factor-Dependent Gene Transcription

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