1. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian Province, China.
2. Department of Neurology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
3. Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, Xiamen, China.
4. Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China.
*These authors contributed equally to this work.
Rationale: Myelin sheath is an important structure to maintain normal functions of the nerves. Nerve Injury-Induced Protein 2 (Ninj2) was found upregulated in Schwann cells (SC) upon injury. However, whether and how Ninj2 plays a role in myelination remain unknown.
Methods: In this study, we use transmission electron microscope imaging, immunofluorescent imaging, and behavioral tests to show the effects of Ninj2 on myelination and remyelination in peripheral nervous system (PNS) of SC-specific Ninj2 knockout mice (Dhhcre/+;Ninj2fl/fl). For mechanism studies, we use RNA-Seq analysis to show the Ninj2-related pathways, and co-immunoprecipitation/mass-spectrometry to identify the Ninj2-interacting proteins in SCs. Furthermore, we evaluate the effect of integrin inhibitor GRGDSP during remyelination.
Results: Ninj2 negatively regulates SC development. Ninj2-deficient mice exhibit precocious myelination phenotype, as well as the accelerated remyelination process after sciatic nerve injury. Loss of Ninj2 promotes myelination by promoting SC proliferation to augment its population. Mechanistically, Ninj2 interacted with ITGB1 on SC membrane, which inhibits laminin-integrin signaling. Removal of Ninj2 induces the activity of laminin-integrin signaling, resulting in the improved myelination in the Dhhcre/+;Ninj2fl/fl mice. Inhibition of laminin-integrin signaling by integrin inhibitor GRGDSP sufficiently delays the remyelination process in the Dhhcre/+;Ninj2fl/fl mice with sciatic nerve injury.
Conclusion: Our study found Ninj2 as a negative regulator in the network controlling myelination in the PNS.
Keywords: Ninj2, Peripheral Nervous System, Myelin, Schwann cell, ITGB1