Jenkins, BE; (2015) The role of c-Jun in Schwann cell morphology and migration. Doctoral thesis , UCL (University College London).

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Abstract

Schwann cells of peripheral nerves undergo significant changes in morphology and gene expression during development and regeneration of the peripheral nervous system (PNS) after nerve injury. This plasticity is associated with the greater regenerative capability of the PNS compared with the CNS. The transcription factor c-Jun is highly expressed in Schwann cells following nerve injury and is required for the reprogramming of mature Schwann cells to become repair Schwann cells that promote regeneration. Mice with a Schwann cell-specific c-Jun deletion fail to generate these repair cells after nerve injury and consequently have a severe failure of axonal regeneration. One striking phenotype of Schwann cells lacking c- Jun is that in culture they lack normal bi- and tri-polar morphology and in the distal stump of injured nerve they form irregular and flattened profiles. I assessed whether the loss of c-Jun affected their ability to migrate, an important property of repair Schwann cells in vivo after nerve injury. Using two complementary in vitro assays, I revealed a significant reduction in cell migration and found that c-Jun deletion caused changes to the actin cytoskeleton and reduced the formation of focal adhesions. Nevertheless, performing quantitative polymerase chain reaction on a number of genes already known to regulate the cytoskeleton failed to reveal differences between RNA from c-Jun knockout Schwann cells and control RNA. I next investigated whether Schwann cell deletion of c-Jun leads to a reduction of Schwann cell migration and axonal outgrowth across the nerve bridge of the transected nerve. I developed an assay to create a nerve bridge that can be replicated easily in size and proximal-distal location. I achieved this by transecting the peroneal branch of the sciatic nerve while leaving the tibial branch intact to support the two nerve stumps. This method provides a useful model of nerve transection. The results reveal that in the c-Jun cKO mouse at 7 days after injury Schwann cells succeeded in migrating across the nerve bridge, but axons show poor re-entry into the distal nerve stump. This requires further investigation.

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