Regulation of a truncated form of tropomyosin-related kinase B (TrkB) by Hsa-miR-185* in frontal cortex of suicide completers.
BACKGROUND
TrkB-T1 is a BDNF receptor lacking a tyrosine kinase domain that is highly expressed in astrocytes and regulates BDNF-evoked calcium transients. Previous studies indicate that downregulation of TrkB-T1 in frontal cortex may be involved in neurobiological processes underlying suicide.


METHODS
In a microarray screening study (N = 8), we interrogated all known microRNA in the frontal cortex of suicide completers with low expression of TrkB-T1 and normal controls. These findings were validated and followed up in a larger sample of cases and controls (N = 55). Functional analyses included microRNA silencing, microRNA overexpression and luciferase assays to investigate specificity and to validate interactions between differentially expressed microRNA and TrkB-T1.


RESULTS
MicroRNAs Hsa-miR-185* and Hsa-miR-491-3p were upregulated in suicide completers with low expression of TrkB.T1 (P(nominal): 9.10(-5) and 1.8.10(-4) respectively; FDR-corrected p = 0.031). Bioinformatic analyses revealed five putative binding sites for the DiGeorge syndrome linked microRNA Hsa-miR-185*in the 3'UTR of TrkB-T1, but none for Hsa-miR-491-3P. The increase of Hsa-miR-185* in frontal cortex of suicide completers was validated then confirmed in a larger, randomly selected group of suicide completers, where an inverse correlation between Hsa-miR-185* and TrkB-T1 expression was observed (R = -0.439; p = 0.001). Silencing and overexpression studies performed in human cell lines confirmed the inverse relationship between hsa-mir-185* and trkB-T1 expression. Luciferase assays demonstrated that Hsa-miR-185* binds to sequences in the 3'UTR of TrkB-T1.


CONCLUSIONS
These results suggest that an increase of Hsa-miR-185* expression levels regulates, at least in part, the TrkB-T1 decrease observed in the frontal cortex of suicide completers and further implicate the 22q11 region in psychopathology.
McGill Group for Suicide Studies, Douglas Hospital Research Institute, McGill University, Montreal, Quebec, Canada.
Gilles
G
Maussion
Jennie
J
Yang
Volodymyr
V
Yerko
Philip
P
Barker
Naguib
N
Mechawar
Carl
C
Ernst
Gustavo
G
Turecki
D020413:3' Untranslated Regions; D001665:Binding Sites; D016022:Case-Control Studies; D002460:Cell Line; D005625:Frontal Lobe / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D013405:Suicide; D014335:Tropomyosin / Q000235:genetics* / Q000378:metabolism
D020413:3' Untranslated Regions; C552431:MIRN185 microRNA, human; C551410:MIRN491 microRNA, human; D035683:MicroRNAs; D014335:Tropomyosin; D011494:Protein Kinases; C041311:tropomyosin kinase