Abstract
Dorsal root ganglia (DRG) neurons spontaneously undergo neurite growth after nerve injury. MicroRNAs (miRNAs), as small, non-coding RNAs, negatively regulate gene expression in a variety of biological processes. The roles of miRNAs in the regulation of responses of DRG neurons to injury stimuli, however, are not fully understood. Here, microarray analysis was performed to profile the miRNAs in L4-L6 DRGs following rat sciatic nerve transection. The 26 known miRNAs were differentially expressed at 0, 1, 4, 7, 14 d post injury, and the potential targets of the miRNAs were involved in nerve regeneration, as analyzed by bioinformatics. Among the 26 miRNAs, microRNA-222 (miR-222) was our research focus because its increased expression promoted neurite outgrowth while it silencing by miR-222 inhibitor reduced neurite outgrowth. Knockdown experiments confirmed that phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a major inhibitor of nerve regeneration, was a direct target of miR-222 in DRG neurons. In addition, we found that miR-222 might regulate the phosphorylation of cAMP response element binding protein (CREB) through PTEN, and c-Jun activation might enhance the miR-222 expression. Collectively, our data suggest that miR-222 could regulate neurite outgrowth from DRG neurons by targeting PTEN.
Highlights
Upon injury to peripheral nerves, the proximal nerve stump will spontaneously regenerate due to activation of the intrinsic growth capacity of neurons
The results showed that there was a significant decrease in neurite outgrowth after transfected with miR-222 inhibitor alone, but a remarkable increase in the longest neurite length and total neurite length after co-transfected with miR-222 inhibitor and small interfering RNAs (siRNAs)-2 against PTEN (Figure 4C), suggesting that PTEN might be a functional mediator for miR-222 in Dorsal root ganglia (DRG) neurons
MiR-223 is highly expressed in neutrophils that are present in the spinal cord during the early phase of spinal cord injury [30]; miR-132 regulates dendritic spine morphology and synaptic physiology, contributes to the maturation of dendrites in newborn neurons in the adult hippocampus, and impacts the plasticity of visual cortex circuits [31,32]; miR-21 is highly expressed in the spinal cord and DRGs following traumatic injury, promoting neurite outgrowth by down-regulating expression of Sprouty2 protein [18,25]
Summary
Upon injury to peripheral nerves, the proximal nerve stump will spontaneously regenerate due to activation of the intrinsic growth capacity of neurons. Once primary sensory neurons are primed by peripheral axonal injury, they grow more rapidly in response to a subsequent lesion, which has been known as the conditioning effect [1,2]. Peripheral ‘‘conditioning’’ lesion switches DRG neurons from a transmitter to a regenerative state, indicating that the robust response of peripheral axons to injury is not merely a ‘‘default’’ state, but results from activation of injury signals, which travel retrogradely from the peripheral lesion site to the cell body and enhance the intrinsic growth capacity of the neurons [8]. The cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response element binding protein (CREB) signaling and the c-Jun transcription factor have been known to activate the intrinsic growth capacity mainly at the transcriptional level after peripheral nerve injury [11,12]. The detailed signaling pathways responsible for the intrinsic regeneration, remain to be further investigated
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