Precisely orchestrated interactions between spinal motor axons and their ensheathing glia are vital for forming and maintaining functional spinal motor nerves. Following perturbations to peripheral myelinating glial cells, centrally-derived oligodendrocyte progenitor cells (OPCs) ectopically exit the spinal cord and myelinate peripheral nerves in myelin with central nervous system (CNS) characteristics. However, whether remaining peripheral ensheathing glia, such as perineurial glia, properly encase the motor nerve despite this change in glial cell and myelin composition, remains unknown. Using zebrafish mutants in which OPCs migrate out of the spinal cord and myelinate peripheral motor axons, we assayed perineurial glial development, maturation and response to injury. Surprisingly, in the presence of OPCs, perineurial glia exited the CNS normally. However, aspects of their development, response to injury and function were altered when compared to wildtype larvae. In an effort to better understand the plasticity of perineurial glia in response to myelin perturbations, we identified transforming growth factor beta 1 (TGF-β1) as a partial mediator of perineurial glial development. Taken together, these results demonstrate the incredible plasticity of perineurial glia in the presence of myelin perturbations.
Peripheral neuropathies can result from damage or dysregulation of the insulating myelin sheath surrounding spinal motor axons, causing pain, inefficient nerve conduction and the ectopic migration of oligodendrocyte progenitor cells (OPCs), the resident myelinating glial cell of the central nervous system (CNS), into the periphery. How perineurial glia, the ensheathing cells that form the protective blood-nerve-barrier (BNB), are impacted by this myelin composition change is unknown. Here, we report that certain aspects of perineurial glial development and injury responses are mostly unaffected in the presence of ectopic OPCs. However, perineurial glial function is disrupted along nerves containing centrally-derived myelin, demonstrating that although perineurial glial cells display plasticity despite myelin perturbations, the blood-nerve-barrier is compromised in the presence of ectopic OPCs.
The authors declare no competing financial interests.
We would like to thank members of the Kucenas laboratory for valuable discussions and Lori Tocke for zebrafish care. For the transmission electron microscopy experiments, we would especially like to thank the following: Dr. Alev Erisir and Erisir laboratory members, Bonnie Sheppard and Drs. Stacey Criswell and Yalin Wang from the UVA Advanced Microscopy Facility. This work was supported by the National Institutes of Health (NIH): NS072212 (SK) and NS051140 (GML), the March of Dimes: 5-FY11-90 (SK) and the Hartwell Foundation (SK).