Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders

Abstract

Genetic and functional data indicate that variation in the expression of the neurotrophin-3 receptor gene (NTRK3) may have an impact on neuronal plasticity suggesting a role for NTRK3 in the pathophysiology of anxiety disorders. MicroRNAs are post-transcriptional gene regulators that act by base pairing to specific sequences, usually at the 3'UTR of the target mRNA. Nucleotide variants at these sites might result in changes of gene expression contributing to disease susceptibility. We have investigated genetic variation in two different isoforms of NTRK3 as candidate susceptibility factors for anxiety by re-sequencing their 3'UTRs in patients with panic disorder, obsessive-compulsive disorder and controls. We have found the C allele of rs28521337, located in a functional target site for miR-485-3p in the truncated isoform of NTRK3, to be significantly associated with the hoarding phenotype of obsessive-compulsive disorder. Furthermore, we have also identified two new rare allelic variants in the 3'UTR of NTRK3, ss102661458 and ss102661460, each present only in a chomosome of a patient with panic disorder. The ss102661458 variant is located in a functional target site for miR-765, and the ss102661460 in functional target sites for two microRNAs, miR-509 and miR-128, the latter being a brain-enriched microRNA involved in neuronal differentiation and synaptic processing. Interestingly, these two variants significantly alter the microRNA-mediated regulation of NTRK3 and result in the recovery of gene expression. The reported data implicate microRNAs as key post-transcriptional regulators of NTRK3 and provide a framework for allele-specific microRNA regulation of NTRK3 in anxiety disorders.

Fibroblast growth factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulnerable animals

“…Interestingly, there is evidence that ntrk3 promotes the survival of postmitotic neurons (22). Moreover, recent studies have linked variations in this gene, SNPs, to anxiety disorders (23)(24)(25). Taken together, these results suggest that ntrk3, which showed a lifelong change in gene expression after FGF2, is involved in cell survival in early hippocampal development and associated with anxiety-like behavior.…”

Basal microRNA expression patterns in reward circuitry of selectively bred high-responder and low-responder rats vary by brain region and genotype

“…Using bioinformatics analyses, we identified a number of experimentally determined interactions between these differentially expressed miRNAs and mRNA targets previously linked to central nervous system functions ( Table 1). Of note, miR-128a and miR-26b have been linked to neurotrophic factor processes in the brain through regulation of the mRNAs for Ntrk3 and Bdnf, respectively (4,30). These associations are potentially interesting given the important role that is emerging for both Ntrk3 and Bdnf in anxiety disorders and drug abuse biology (27,42).…”

MicroRNA expression profiling in benign (sporadic and hereditary) and recurring adrenal pheochromocytomas

“…miR-765 might target neurotrophin-3 receptor (NTRK3, also known as TRKC). 31 In the PC12 rat pheochromocytoma cell line expressing neurotrophin receptors, neurotrophin-3 (NTF3) activates the Erk1/2 and Erk5 pathways, 32 and induces moderate neurite overgrowth and neuron-like differentiation of PC12 cells. 33 Overexpression of miR-765 and the consequent NTRK3 underexpression might thus be hypothesized to be involved in pheochromocytoma pathogenesis.…”