Human-Specific Regulation of Neurotrophic Factors MANF and CDNF by microRNAs

International Journal of Molecular Sciences

Sven Kluske¹  Alba Vargas Pereyra¹  Julia Konovalova¹  Dmytro Gerasymchuk¹  Andrii Domanskyi¹  Sergio Navarette Arroyo¹  Francesca Mastroianni¹ 

[1] Institute of Biotechnology, HiLIFE, University of Helsinki, Viikinkaari 5D, 00790 Helsinki, Finland;

关键词: mesencephalic astrocyte derived neurotrophic factor;    MANF;    cerebral dopamine neurotrophic factor;    CDNF;    microRNAs;    3′UTR;   

DOI  :  10.3390/ijms22189691

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown