Spinal motor nerves are necessary for organismal locomotion and survival.In zebrafish and most vertebrates, these peripheral nervous system structures are composed of bundles of axons that naturally regenerate following injury. However, the cellular and molecular mechanisms that mediate this process are still only partially understood. Perineurial glia, which form a component of the blood-nerve barrier, are necessary for the earliest regenerative steps by establishing a glial bridge across the injury site as well as phagocytosing debris. Without perineurial glial bridging, regeneration is impaired. In addition to perineurial glia, Schwann cells, the cells that ensheath and myelinate axons within the nerve, are essential for debris clearance and axon guidance. In the absence of Schwann cells, perineurial glia exhibit perturbed bridging, demonstrating that these two cell types communicate during the injury response.While the presence and importance of perineurial glial bridging is known, the molecular mechanisms that underlie this process remain a mystery. Understanding the cellular and molecular interactions that drive perineurial glial bridging is crucial to unlocking the mechanisms underlying successful motor nerve regeneration. Using laser axotomy and in vivo imaging in zebrafish, we show that transforming growth factor-beta (TGFβ) signaling modulates perineurial glial bridging. Further, we identify connective tissue growth factor-a (ctgfa) as a downstream effector of TGF-β signaling that works in a positive feedback loop to mediate perineurial glial bridging. Together, these studies present a new signaling pathway involved in the perineurial glial injury response and further characterize the dynamics of the perineurial glial bridge.
While glia were once thought to be nothing more than glue‐like cells that hold the nervous system together, there is growing evidence that signals to and from glia are indispensable for development, cell‐to‐cell communication and maintenance of efficient nervous system function. Several studies show that glia often receive conflicting signals during disease progression and can play dual roles as both antagonists and neuroprotectors in distinct settings. Key Concepts Glia play neuroprotective and neurodegenerative role during the initiation and progression stage of neurodegenerative diseases. Astrocytes mediate calcium‐related neurotoxicity in Alzheimer's disease. Microglia regulate neurodegeneration in Parkinson's disease through NO‐related apoptotic pathway. Oligodendrocytes and Schwann cells regulate myelin wasting diseases in central and peripheral nervous system through Wnt and ErbB2/ErbB3 signalling pathways. Glial cells form a scar following spinal cord injury that affects regenerative abilities.
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