PMID- 29522201
OWN - NLM
STAT- MEDLINE
DCOM- 20190429
LR  - 20190429
IS  - 1096-0929 (Electronic)
IS  - 1096-0929 (Linking)
VI  - 163
IP  - 2
DP  - 2018 Jun 1
TI  - The miR206-JunD Circuit Mediates the Neurotoxic Effect of Methylmercury in 
      Cortical Neurons.
PG  - 569-578
LID - 10.1093/toxsci/kfy051 [doi]
AB  - Methylmercury (MeHg) causes neuronal death through different pathways. 
      Particularly, we found that in cortical neurons it increased the expression of 
      Repressor Element-1 Silencing Transcription Factor (REST), histone deacetylase 
      (HDAC)4, Specificity Protein (Sp)1, Sp4, and reduced the levels of brain-derived 
      neurotrophic factor (BDNF). Herein, in rat cortical neurons we investigated 
      whether microRNA (miR)206 can modulate MeHg-induced cell death by regulating 
      REST/HDAC4/Sp1/Sp4/BDNF axis. MeHg (1 microM) reduced miR206 expression after both 12 
      and 24 h and miR206 transfection prevented MeHg-induced neuronal death. 
      Furthermore, miR206 reverted MeHg-induced REST and Sp4 increase and BDNF 
      reduction at gene and protein level, and reverted HDAC4 protein increase, but not 
      HDAC4 mRNA upregulation. Moreover, since no miR206 seed sequences were identified 
      in the 3'-untranslated regions (3'-UTRs) of REST and SP4, we investigated the 
      role of JunD, that presents a consensus motif on REST, Sp4, and BDNF promoters. 
      Indeed, MeHg increased JunD mRNA and protein levels, and JunD knockdown 
      counteracted MeHg-induced REST, Sp4 increase, but not BDNF reduction. 
      Furthermore, we identified a miR206 binding site in the 3'-UTR of JunD mRNA 
      (miR206/JunD) and mutagenesis of miR206/JunD site reverted JunD luciferase 
      activity reduction induced by miR206. Finally, miR206 prevented MeHg-increased 
      JunD binding to REST and Sp4 promoters, and MeHg-reduced BDNF expression was 
      determined by the increase of HDAC4 binding on BDNF promoter IV. Collectively, 
      these results suggest that miR206 downregulation induced by MeHg exposure 
      determines an upregulation of HDAC4, that in turn downregulated BDNF, and the 
      activation of JunD that, by binding REST and Sp4 gene promoters, increased their 
      expression.
FAU - Guida, Natascia
AU  - Guida N
AD  - IRCCS SDN, 80143 Naples, Italy.
FAU - Valsecchi, Valeria
AU  - Valsecchi V
AD  - Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry 
      Sciences, School of Medicine, "Federico II" University of Naples, 80131 Naples, 
      Italy.
FAU - Laudati, Giusy
AU  - Laudati G
AD  - Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry 
      Sciences, School of Medicine, "Federico II" University of Naples, 80131 Naples, 
      Italy.
AD  - Division of Pharmacology, Department of Science and Technology, University of 
      Sannio, 82100 Benevento, Italy.
FAU - Serani, Angelo
AU  - Serani A
AD  - Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry 
      Sciences, School of Medicine, "Federico II" University of Naples, 80131 Naples, 
      Italy.
FAU - Mascolo, Luigi
AU  - Mascolo L
AD  - Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry 
      Sciences, School of Medicine, "Federico II" University of Naples, 80131 Naples, 
      Italy.
FAU - Molinaro, Pasquale
AU  - Molinaro P
AD  - Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry 
      Sciences, School of Medicine, "Federico II" University of Naples, 80131 Naples, 
      Italy.
FAU - Montuori, Paolo
AU  - Montuori P
AD  - Department of Preventive Medical Sciences, University Federico II, 80131 Naples, 
      Italy.
FAU - Di Renzo, Gianfranco
AU  - Di Renzo G
AD  - Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry 
      Sciences, School of Medicine, "Federico II" University of Naples, 80131 Naples, 
      Italy.
FAU - Canzoniero, Lorella M
AU  - Canzoniero LM
AD  - Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry 
      Sciences, School of Medicine, "Federico II" University of Naples, 80131 Naples, 
      Italy.
AD  - Division of Pharmacology, Department of Science and Technology, University of 
      Sannio, 82100 Benevento, Italy.
FAU - Formisano, Luigi
AU  - Formisano L
AD  - Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry 
      Sciences, School of Medicine, "Federico II" University of Naples, 80131 Naples, 
      Italy.
AD  - Division of Pharmacology, Department of Science and Technology, University of 
      Sannio, 82100 Benevento, Italy.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (3' Untranslated Regions)
RN  - 0 (Methylmercury Compounds)
RN  - 0 (MicroRNAs)
RN  - 0 (Proto-Oncogene Proteins c-jun)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (mirn206 microRNA, rat)
RN  - RWZ4L3O1X0 (methylmercuric chloride)
SB  - IM
MH  - 3' Untranslated Regions/genetics
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Cerebral Cortex/*drug effects/metabolism/pathology
MH  - Humans
MH  - Methylmercury Compounds/*toxicity
MH  - MicroRNAs/genetics/*metabolism
MH  - Neurons/*drug effects/metabolism/pathology
MH  - Neurotoxicity Syndromes/*metabolism/pathology
MH  - Proto-Oncogene Proteins c-jun/genetics/*metabolism
MH  - RNA, Small Interfering/genetics
MH  - Rats
MH  - Transfection
EDAT- 2018/03/10 06:00
MHDA- 2019/04/30 06:00
CRDT- 2018/03/10 06:00
PHST- 2018/03/10 06:00 [pubmed]
PHST- 2019/04/30 06:00 [medline]
PHST- 2018/03/10 06:00 [entrez]
AID - 4924553 [pii]
AID - 10.1093/toxsci/kfy051 [doi]
PST - ppublish
SO  - Toxicol Sci. 2018 Jun 1;163(2):569-578. doi: 10.1093/toxsci/kfy051.