Role of miR-17-92 in the functional changes of primary sensory neurons following nerve injury

[Speaker] Atsushi Sakai:1
[Co-author] Fumihito Saitow:1, Motoyo Maruyama:1,2, Noriko Miyake:3, Koichi Miyake:3, Takashi Okada:3, Hidenori Suzuki:1
1:Department of Pharmacology, Nippon Medical School, Japan, 2:Division of Laboratory Animal Science, Nippon Medical School, Japan, 3:Department of Biochemistry and Molecular Biology, Nippon Medical School, Japan

MicroRNA is a small non-coding RNA that generally inhibits protein translation of multiple genes in a sequence-specific manner. miR-17-92 is a microRNA cluster that encodes six distinct microRNAs in its primary transcript and is therefore considered to affect a wide range of cellular functions. Here, we demonstrate a role of miR-17-92 in the primary sensory neurons after nerve injury, which causes characteristic phenomena including chronic neuropathic pain and enhanced axonal outgrowth. miR-17-92 expression was persistently upregulated in the primary sensory neurons after spinal nerve injury in rats. To address the pathophysiological relevance of miR-17-92 upregulation in the primary sensory neurons, we transduced an adeno-associated viral (AAV) vector encoding miR-17-92 specifically into the primary sensory neurons of intact rats. miR-17-92 overexpression caused mechanical pain, while enhanced the axonal outgrowth in vitro. Microarray analysis revealed that miR-17-92 overexpression affected many gene expressions, which included both predicted miR-17-92 target and non-target genes. Bioinformatics indicated that these differentially expressed genes were associated with nervous system development and function. Consistent with this, miR-17-92 directly modulated the expression levels of multiple voltage-gated potassium channels and their modulatory subunits, which were critical modulators for excitability of nociceptive neurons. miR-17-92 inhibition restored the decreased potassium current and neuropathic pain behavior. These results suggest that miR-17-92 coordinates the functional changes of primary sensory neurons following nerve injury and therefore may provide better therapeutic strategy for peripheral nerve injury.
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