Edited by Ronald C. Wek Axon guidance helps growing neural axons to follow precise paths to reach their target locations. It is a critical step for both the formation and regeneration of neuronal circuitry. Netrin-1 (Ntn1) and its receptor, deleted in colorectal carcinoma (Dcc) are essential factors for axon guidance, but their regulation in this process is incompletely understood. In this study, using quantitative real-time RT-PCR (qRT-PCR) and biochemical and reporter gene assays, we found that the Ntn1 and Dcc genes are both robustly up-regulated in the sciatic nerve stump after peripheral nerve injury. Moreover, we found that the microRNA (miR) let-7 directly targets the Ntn1 transcript by binding to its 3-untranslated region (3-UTR), represses Ntn1 expression, and reduces the secretion of Ntn1 protein in Schwann cells. We also identified miR-9 as the regulatory miRNA that directly targets Dcc and found that miR-9 down-regulates Dcc expression and suppresses the migration ability of Schwann cells by regulating Dcc abundance. Functional examination in dorsal root ganglion neurons disclosed that let-7 and miR-9 decrease the protein levels of Ntn1 and Dcc in these neurons, respectively, and reduce axon outgrowth. Moreover, we identified a potential regulatory network comprising let-7, miR-9, Ntn1, Dcc, and related molecules, including the RNA-binding protein Lin-28 homolog A (Lin28), SRC proto-oncogene nonreceptor tyrosine kinase (Src), and the transcription factor NF-B. In summary, our findings reveal that the miRs let-7 and miR-9 are involved in regulating neuron pathfinding and extend our understanding of the regulatory pathways active during peripheral nerve regeneration.
Peripheral nerves are composed of complex layered anatomical structures, including epineurium, perineurium, and endoneurium. Perineurium and endoneurium contain many physical barriers, including the blood-nerve barrier at endoneurial vessels and the perineurial barrier. These physical barriers help to eliminate flux penetration and thus contribute to the establishment of a stable microenvironment. In the current review, we introduce the anatomical compartments and physical barriers of peripheral nerves and then describe the cellular and molecular basis of peripheral physical barriers. We also specifically explore peripheral nerve injury-induced changes of peripheral physical barriers, including elevated endoneurial fluid pressure, increased leakage of tracer, decreased barrier-type endothelial cell ratio, and altered distributions and expressions of cellular junctional proteins. The understanding of the pathophysiological changes of physical barriers following peripheral nerve injury may provide a clue for the treatment of peripheral nerve injury.
Tau protein (encoded by the gene microtubule-associated protein tau, Mapt) is essential for the assembly and stability of microtubule and the functional maintenance of the nervous system. Tau is highly abundant in neurons and is detectable in astrocytes and oligodendrocytes. However, whether tau is present in Schwann cells, the unique glial cells in the peripheral nervous system, is unclear. Here, we investigated the presence of tau and its coding mRNA, Mapt, in cultured Schwann cells and find that tau is present in these cells. Gene silencing of Mapt promoted Schwann cell proliferation and inhibited Schwann cell migration and differentiation. In vivo application of Mapt siRNA suppressed the migration of Schwann cells after sciatic nerve injury. Consistent with this, Mapt-knockout mice showed elevated proliferation and reduced migration of Schwann cells. Rats injected with Mapt siRNA and Mapt-knockout mice also exhibited impaired myelin and lipid debris clearance. The expression and distribution of the cytoskeleton proteins α-tubulin and F-actin were also disrupted in these animals. These findings demonstrate the existence and biological effects of tau in Schwann cells, and expand our understanding of the function of tau in the nervous system.
Leukemia inhibitory factor (LIF) is a pleiotropic cytokine that stimulates neuronal development and survival. Our previous study has demonstrated that LIF mRNA is dysregulated in the peripheral nerve segments after nerve injury. Here, we show that LIF protein is abundantly expressed in Schwann cells after rat sciatic nerve injury. Functionally, suppressed or elevated LIF increases or decreases the proliferation rate and migration ability of Schwann cells, respectively. Morphological observations demonstrate that in vivo application of siRNA against LIF after peripheral nerve injury promotes Schwann cell migration and proliferation, axon elongation, and myelin formation. Electrophysiological and behavior assessments disclose that knockdown of LIF benefits the function recovery of injured peripheral nerves. Differentially expressed LIF affects the metabolism of Schwann cells and negatively regulates ERFE (Erythroferrone). Collectively, our observations reveal the essential roles for LIF in regulating the proliferation and migration of Schwann cells and the regeneration of injured peripheral nerves, discover ERFE as a downstream effector of LIF, and extend our understanding of the molecular mechanisms underlying peripheral nerve regeneration.
Peripheral nerve injury is a worldwide clinical issue that impacts patients’ quality of life and causes huge society and economic burden. Injured peripheral nerves are able to regenerate by themselves. However, for severe peripheral nerve injury, the regenerative abilities are very limited and the regenerative effects are very poor. A better understanding of the mechanisms following peripheral nerve injury will benefit its clinical treatment. In this study, we systematically explored the dynamic changes of mRNAs and long non-coding RNAs (lncRNAs) in the injured sciatic nerve segments after nerve crush, identified significantly involved Gene ontology (GO) terms and Kyoto Enrichment of Genes and Genomes (KEGG) pathways, and innovatively analyzed the correlation of differentially expressed mRNAs and lncRNAs. After the clustering of co-expressed mRNAs and lncRNAs, we performed functional analysis, selected GO term “negative regulation of cell proliferation”, and constructed a competing endogenous RNA (ceRNA) network of LIF and HMOX1 gene in this GO term. This study is the first to provide a systematic dissection of mRNA-microRNA (miRNA)-lncRNA ceRNA network following peripheral nerve injury and thus lays a foundation for further investigations of the regulating mechanisms of non-coding RNAs in peripheral nerve repair and regeneration.Electronic supplementary materialThe online version of this article (10.1186/s13041-018-0421-4) contains supplementary material, which is available to authorized users.
The temporal patterns of pro-inflammatory and anti-inflammatory macrophages after peripheral nerve injury.
Tight junctions seal off physical barriers, regulate fluid and solute flow, and protect the endoneurial microenvironment of the peripheral nervous system. Physical barriers in the peripheral nervous system were disrupted after nerve injury. However, the dynamic changes of tight junction components after peripheral nerve injury have not been fully determined yet. In the current study, by using previously obtained deep sequencing outcomes and bioinformatic tools, we found that tight junction signaling pathway was activated after peripheral nerve injury. The investigation of the temporal expression patterns of components in tight junction signaling pathway suggested that many claudin family members were down-regulated after nerve injury. Moreover, we examined the effects of matrix metalloproteinases 7 and 9 (MMP7 and MMP9) on tight junction genes both in vitro and in vivo and found that MMP7 and MMP9 modulated the expressions of genes coding for claudin 1, claudin 10, and claudin 22. Our study revealed the dynamic changes of tight junction components after peripheral nerve injury and thus might contribute to the understanding of the molecular mechanisms underlying peripheral nerve injury and regeneration.
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