Methylmercury upregulates RE-1 silencing transcription factor (REST) in SH-SY5Y cells and mouse cerebellum

Guida, Natascia; Laudati, Giusy; Anzilotti, Serenella; Sirabella, Rossana; Cuomo, Ornella; Brancaccio, Paola; Santopaolo, Marianna; Galgani, Mario; Montuori, Paolo; Renzo, Gianfranco Di; Canzoniero, Lorella M.T.; Formisano, Luigi

doi:10.1016/j.neuro.2015.11.007

Cited by 33 publications

(30 citation statements)

References 42 publications

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“…We previously found reduced expression of REST-targeted pro-neural transcription factors in the adult male brain; thus, it is likely that dysregulation of REST, perhaps early in the embryonic development, results in aberrant programming of regulatory factors responsible for appropriate NSC differentiation in the adult hippocampus [56]. To our knowledge there are no known reports assessing the effect of arsenic on REST expression in the brain; however, our findings are corroborated by a recent study on methylmercury exposure demonstrating increased expression of REST and CoREST in the mouse cerebellum [19]. Additionally, in vitro exposure to sodium arsenite exposure inhibits early differentiation of neural plate border cells and reduces Neurod1, which is a RESTregulated transcription factor [16,39].…”

Section: Discussionsupporting

confidence: 80%

Prenatal arsenic exposure alters REST/NRSF and microRNA regulators of embryonic neural stem cell fate in a sex-dependent manner

Tyler

Labrecque

Solomon

et al. 2017

Neurotoxicology and Teratology

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Exposure to arsenic, a common environmental toxin found in drinking water, leads to a host of neurological pathologies. We have previously demonstrated that developmental exposure to a low level of arsenic (50 ppb) alters epigenetic processes that underlie deficits in adult hippocampal neurogenesis leading to aberrant behavior. It is unclear if arsenic impacts the programming and regulation of embryonic neurogenesis during development when exposure occurs. The master negative regulator of neural-lineage, REST/NRSF, controls the precise timing of fate specification and differentiation of neural stem cells (NSCs). Early in development (embryonic day 14), we observed increased expression of Rest, its co-repressor, CoREST, and the inhibitory RNA binding/splicing protein, Ptbp1, and altered expression of mRNA spliced isoforms of Pbx1 that are directly regulated by these factors in the male brain in response to prenatal 50 ppb arsenic exposure. These increases were concurrent with decreased expression of microRNA-9 (miR-9), miR-9*, and miR-124, all of which are REST/NRSF targets and inversely regulate Rest expression to allow for maturation of NSCs. Exposure to arsenic decreased the formation of neuroblasts in vitro from NSCs derived from male pup brains. The female response to arsenic was limited to increased expression of CoREST and Ptbp2, an RNA binding protein that allows for appropriate splicing of genes involved in the progression of neurogenesis. These changes were accompanied by increased neuroblast formation in vitro from NSCs derived from female pups. Unexposed male mice express transcriptomic factors to induce differentiation earlier in development compared to unexposed females. Thus, arsenic exposure likely delays differentiation of NSCs in males while potentially inducing precocious differentiation in females early in development. These effects are mitigated by embryonic day 18 of development. Arsenic-induced dysregulation of the regulatory loop formed by REST/NRSF, its target microRNAs, miR-9 and miR-124, and RNA splicing proteins, PTBP1 and 2, leads to aberrant programming of NSC function that is perhaps perpetuated into adulthood inducing deficits in differentiation we have previously observed.

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Section: Discussionsupporting

confidence: 80%

Prenatal arsenic exposure alters REST/NRSF and microRNA regulators of embryonic neural stem cell fate in a sex-dependent manner

Tyler

Labrecque

Solomon

et al. 2017

Neurotoxicology and Teratology

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“…Methylmercury (II) chloride (MeHg) (cod: 442534 stock solution 100 μM) and p38 inhibitor SB239063 (SB) (cod: 559404 stock solution 10 mM) were both dissolved in vehicle as previously reported (Sirabella et al, 2012; Guida et al, 2015b). Culture media and sera were purchased from Invitrogen (Milan, Italy).…”

Section: Methodsmentioning

confidence: 99%

“…The experiments on primary cortical neurons were performed according to the experimental protocols approved by the Ethics Committee of “Federico II” University of Naples. SH-SY5Y cells were incubated in a low serum medium (Guida et al, 2015b) and treated with MeHg 1 μM at 12 and 24 h. For dose-dependent experiments, primary cortical neurons were treated for 24 h with MeHg at 0.1, 0.5, 1, and 3 μM. For SB239063 experiments cells were pre-treated for 2 h with the drug at 10 μM followed with MeHg 1 μM for 24 h. All transfection experiments in SH-SY5Y and cortical neurons were performed 24 h before MeHg treatment (1 μM/24 h) with HiPerFect Transfection Reagent (Quiagen) in accordance with the manufacture's protocol, as previously reported (Vinciguerra et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

“…In fact, it has been demonstrated that HDACs 1, 2, and 4 exert a neurotoxic effect after brain ischemia (Formisano et al, 2015b; Yuan et al, 2016), HDAC3 and HDAC5 can induce cell death of cerebellar granule neurons (CGN) (Bardai and D'Mello, 2011), and HDAC6 inhibition protects against oxidative stress-induced neurodegeneration (Rivieccio et al, 2009). On the other hand a pan HDAC inhibition has been found to be neuroprotective in vitro against the neurotoxicity of bis (2-ethylhexyl) phthalate (DEHP) (Guida et al, 2014), Polychlorinated Biphenyls (PCB) (Formisano et al, 2011, 2015a), and MeHg (Guida et al, 2015b). Recently, it has also been shown that the mercury-containing organic compound Thimerosal induces an increase of the HDAC4 isoform (Guida et al, 2015b, 2016) determining neuronal cell death, but the molecular mechanism of this effect is still unrevealed.…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand a pan HDAC inhibition has been found to be neuroprotective in vitro against the neurotoxicity of bis (2-ethylhexyl) phthalate (DEHP) (Guida et al, 2014), Polychlorinated Biphenyls (PCB) (Formisano et al, 2011, 2015a), and MeHg (Guida et al, 2015b). Recently, it has also been shown that the mercury-containing organic compound Thimerosal induces an increase of the HDAC4 isoform (Guida et al, 2015b, 2016) determining neuronal cell death, but the molecular mechanism of this effect is still unrevealed. On the other hand, it is known that HDAC4 mRNA expression is regulated by the transcription factors specificity proteins 1 (Sp1) and 3 (Sp3) (Liu et al, 2006), that have been also associated in vivo to neuronal cell death after stroke (Formisano et al, 2015b), and in vitro to cell death after PCB exposure, through the up-regulation of RE1-Silencing Transcription factor (REST) (Formisano et al, 2015c).…”

Section: Introductionmentioning

confidence: 99%

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p38/Sp1/Sp4/HDAC4/BDNF Axis Is a Novel Molecular Pathway of the Neurotoxic Effect of the Methylmercury

et al. 2017

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The molecular pathways involved in methylmercury (MeHg)-induced neurotoxicity are not fully understood. Since pan-Histone deacetylases (HDACs) inhibition has been found to revert the neurodetrimental effect of MeHg, it appeared of interest to investigate whether the pattern of HDACs isoform protein expression is modified during MeHg-induced neurotoxicity and the transcriptional/transductional mechanisms involved. SH-SY5Y neuroblastoma cells treated with MeHg 1 μM for 12 and 24 h showed a significant increase of HDAC4 protein and gene expression, whereas the HDACs isoforms 1–3, 5, and 6 were unmodified. Furthermore, MeHg-induced HDAC4 increase was reverted when cells were transfected with siRNAs against specificity protein 1 (Sp1) and Sp4, that were both increased during MeHg exposure. Next we studied the role of extracellular-signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK), and p38 mitogen-activated protein kinases (MAPKs) in MeHg—induced increase of Sp1, Sp4, and HDAC4 expression. As shown by Western Blot analysis MeHg exposure increased the phosphorylation of p38, but not of ERK and JNK. Notably, when p38 was pharmacologically blocked, MeHg-induced Sp1, Sp4 protein expression, and HDAC4 protein and gene expression was reverted. In addition, MeHg exposure increased the binding of HDAC4 to the promoter IV of the Brain-derived neurotrophic factor (BDNF) gene, determining its mRNA reduction, that was significantly counteracted by HDAC4 knocking down. Furthermore, rat cortical neurons exposed to MeHg (1 μM/24 h) showed an increased phosphorylation of p38, in parallel with an up-regulation of Sp1, Sp4, and HDAC4 and a down-regulation of BDNF proteins. Importantly, transfection of siRNAs against p38, Sp1, Sp4, and HDAC4 or transfection of vector overexpressing BDNF significantly blocked MeHg-induced cell death in cortical neurons. All these results suggest that p38/Sp1-Sp4/HDAC4/BDNF may represent a new pathway involved in MeHg-induced neurotoxicity.

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The functions of repressor element 1-silencing transcription factor in models of epileptogenesis and post-ischemia

Butler-Ryan

Wood

2021

Metab Brain Dis

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Epilepsy is a debilitating neurological disorder characterised by recurrent seizures for which 30% of patients are refractory to current treatments. The genetic and molecular aetiologies behind epilepsy are under investigation with the goal of developing new epilepsy medications. The transcriptional repressor REST (Repressor Element 1-Silencing Transcription factor) is a focus of interest as it is consistently upregulated in epilepsy patients and following brain insult in animal models of epilepsy and ischemia. This review analyses data from different epilepsy models and discusses the contribution of REST to epileptogenesis. We propose that in healthy brains REST acts in a protective manner to homeostatically downregulate increases in excitability, to protect against seizure through downregulation of BDNF (Brain-Derived Neurotrophic Factor) and its receptor, TrkB (Tropomyosin receptor kinase B). However, in epilepsy patients and post-seizure, REST may increase to a larger degree, which allows downregulation of the glutamate receptor subunit GluR2. This leads to AMPA glutamate receptors lacking GluR2 subunits, which have increased permeability to Ca2+, causing excitotoxicity, cell death and seizure. This concept highlights therapeutic potential of REST modulation through gene therapy in epilepsy patients.

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Methylmercury upregulates RE-1 silencing transcription factor (REST) in SH-SY5Y cells and mouse cerebellum

Cited by 33 publications

References 42 publications

Prenatal arsenic exposure alters REST/NRSF and microRNA regulators of embryonic neural stem cell fate in a sex-dependent manner

Prenatal arsenic exposure alters REST/NRSF and microRNA regulators of embryonic neural stem cell fate in a sex-dependent manner

p38/Sp1/Sp4/HDAC4/BDNF Axis Is a Novel Molecular Pathway of the Neurotoxic Effect of the Methylmercury

The functions of repressor element 1-silencing transcription factor in models of epileptogenesis and post-ischemia

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