Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs that function as key post-transcriptional regulators in neural development, brain function, and neurological diseases. Growing evidence indicates that miRNAs are also important mediators of nerve regeneration, however, the affected signaling mechanisms are not clearly understood. In the present study, we show that nerve injury-induced miR-431 stimulates regenerative axon growth by silencing Kremen1, an antagonist of Wnt/beta-catenin signaling. Both the gain-of-function of miR-431 and knockdown of Kremen1 significantly enhance axon outgrowth in murine dorsal root ganglion neuronal cultures. Using cross-linking with AGO-2 immunoprecipitation, and 3′-untranslated region (UTR) luciferase reporter assay we demonstrate miR-431 direct interaction on the 3′-UTR of Kremen1 mRNA. Together, our results identify miR-431 as an important regulator of axonal regeneration and a promising therapeutic target.
Highlights
Axon loss is the hallmark of traumatic brain and spinal cord injury (SCI) as well as many neurodegenerative diseases including Alzheimer’s (Coleman and Perry, 2002)
Growing evidence indicates that microRNA pathway controls regulatory mechanism involved in neural repair and regeneration (Strickland et al, 2011; Wu et al, 2011, 2012; Yu et al, 2011a; Zhang et al, 2011; Zhou et al, 2012). miRNAs are short, non-coding RNAs that silence gene expression by imperfect binding to 3 -untranslated region (UTR) of mRNA (Bartel, 2004; Filipowicz et al, 2008). miRNAs ability to simultaneously regulate the expression of several genes suggests that they are critical regulators of complex transcriptional networks (McNeill and Van Vactor, 2012)
ALTERED miRNA EXPRESSION FOLLOWING NERVE INJURY Our microarray experiments identified a group of injury-regulated miRNAs in dorsal root ganglia (DRG) neurons after conditioning sciatic nerve lesion
Summary
Axon loss is the hallmark of traumatic brain and spinal cord injury (SCI) as well as many neurodegenerative diseases including Alzheimer’s (Coleman and Perry, 2002). Growing evidence indicates that microRNA (miRNA) pathway controls regulatory mechanism involved in neural repair and regeneration (Strickland et al, 2011; Wu et al, 2011, 2012; Yu et al, 2011a; Zhang et al, 2011; Zhou et al, 2012). Several miRNAs have been associated with axon regeneration in peripheral nervous system (PNS) neurons (Strickland et al, 2011; Yu et al, 2011a; Zhang et al, 2011; Zhou et al, 2012) and axon development in cortical neurons (Dajas-Bailador et al, 2012)
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