Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 294, Issue 10, Pages 3489-3500Publisher
ELSEVIER
DOI: 10.1074/jbc.RA119.007389
Keywords
axon; microRNA (miRNA); regeneration; Schwann cells; neuron; translation regulation; deleted in colorectal carcinoma; let-7; miR-9; Netrin-1; peripheral nerve regeneration
Categories
Funding
- National Key RAMP
- D Program of China [2017YFA0104703]
- National Key Research and Development Program of China [31730031]
- Collegiate Natural Science Fund of Jiangsu Province [16KJA310005]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
- Natural Science Foundation of Nantong Grant [MS12017015-2]
- Postgraduate Research AMP
- Practice Innovation Program of Jiangsu Province [KYCX18-2398]
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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.
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