Human-Specific Regulation of Neurotrophic Factors MANF and CDNF by microRNAs
| Autor: | Konovalova, Julia, Gerasymchuk, Dmytro, Arroyo, Sergio Navarette, Kluske, Sven, Mastroianni, Francesca, Pereyra, Alba Vargas, Domanskyi, Andrii |
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| Přispěvatelé: | Division of Pharmacology and Pharmacotherapy, Institute of Biotechnology, Neuroscience Center, Biosciences |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
3 ' UTR
QH301-705.5 BIOGENESIS BIOMARKERS cerebral dopamine neurotrophic factor 3′UTR mesencephalic astrocyte derived neurotrophic factor Article RNAS Cell Line CDNF TARGETS human-specific regulation Humans Nerve Growth Factors RNA Messenger Biology (General) NEURONS 3' Untranslated Regions QD1-999 MANF ER STRESS Endoplasmic Reticulum Stress microRNAs Chemistry Gene Expression Regulation 1182 Biochemistry cell and molecular biology RNA Interference |
| Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 18 International Journal of Molecular Sciences, Vol 22, Iss 9691, p 9691 (2021) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms22189691 |
| Popis: | Mesencephalic astrocyte derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) are novel evolutionary conserved trophic factors, which exhibit cytoprotective activity via negative regulation of unfolded protein response (UPR) and inflammation. Despite multiple reports demonstrating detrimental effect of MANF/CDNF downregulation, little is known about the control of their expression. miRNAs—small non-coding RNAs—are important regulators of gene expression. Their dysregulation was demonstrated in multiple pathological processes and their ability to modulate levels of other neurotrophic factors, glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), was previously reported. Here, for the first time we demonstrated direct regulation of MANF and CDNF by miRNAs. Using bioinformatic tools, reporter assay and analysis of endogenous MANF and CDNF, we identified that miR-144 controls MANF expression, and miR-134 and miR-141 downregulate CDNF levels. We also demonstrated that this effect is human-specific and is executed via predicted binding sites of corresponding miRNAs. Finally, we found that miR-382 suppressed hCDNF expression indirectly. In conclusion, we demonstrate for the first time direct regulation of MANF and CDNF expression by specific miRNAs, despite the fact their binding sites are not strongly evolutionary conserved. Furthermore, we demonstrate a functional effect of miR-144 mediated regulation of MANF on ER stress response markers. These findings emphasize that (1) prediction of miRNA targets based on evolutionary conservation may miss biologically meaningful regulatory pairs and (2) interpretation of miRNA regulatory effects in animal models should be cautiously validated. |
| Databáze: | OpenAIRE |
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