Abstract

Schwann cells are the principal glial cell of the peripheral nervous system and are responsible for axon maintenance, regeneration and increasing saltatory conduction of neurons. Schwann cell differentiation and myelination is mediated by a core network of transcription factors and signalling pathways, which have been divided into two groups; positive and negative regulators. Sox10, NFATc4, Oct6, Krox20 and the ERK 1/2 signalling pathway have been characterised as positive regulators of Schwann cell differentiation and myelination; with Sox10 and Krox20 also playing critical roles in myelin maintenance. On the other hand, transcription factors cJun, Pax3, Id2 and signalling pathways Notch and p38 mitogen activated protein (MAP) kinases (MAPK) have been identified as negative regulators of Schwann cell differentiation and myelin formation. Recently, the HMG transcription factor Sox2 was identified as a negative regulator of Schwann cell myelination in vitro, however its role in Schwann cell myelination in vivo has not yet been studied. This study therefore aimed to examine the role of Sox2 overexpression in Schwann cells and how it effects Schwann cell differentiation and myelination during development and after injury. In addition, we aimed to investigate for the first time the specific role of p38α (the major isoform of p38 MAPK) in Schwann cell myelination in vivo, by generating Schwann cell specific p38α conditional knockout mice. Sox2 is highly expressed in immature Schwann cells, but is downregulated as Schwann cells being to mature and differentiate. This study shows that continued expression of Sox2 during development and after injury, impairs Schwann cell differentiation and myelination by directly downregulating the expression of two core transcription factors; Sox10 and Krox20, as well as myelin proteins, P0 and MBP. In addition, we observe that continued Sox2 expression significantly increases Schwann cell proliferation and maintains Schwann cells in an immature state. Unexpectedly, we also observed that continued Sox2 expression significantly increases the number of macrophages present in the nerves of Sox2 overexpressing mice at both P60 and 21 days post injury. Phenotypically, Sox2 overexpressing mice 6 show signs of a peripheral neuropathy and animals have impaired motor and sensory function. These findings confirm that Sox2 is a negative regulator of Schwann cell myelination and suggests that continued Sox2 expression is sufficient to drive the progressive development of a peripheral nerve disorder which may resemble Charcot-Marie-Tooth type 1 demyelinating neuropathy and congenital hypomyelinating neuropathy. As a negative regulator of Schwann cell myelination, activity of the p38 MAPK pathway has been shown to inhibit myelin formation in vitro and to also induce the Schwann cell injury response; by driving Schwann cell dedifferentiation and demyelination following injury. Here we show that specific removal of the p38α isoform in Schwann cells leads to an increase in myelin thickness at early developmental time-points, along with an elevated expression of myelin proteins, P0 and MBP. Further analysis following nerve injury revealed that removal of p38α results in an initial decrease in Schwann cell demyelination, yet improves axon remyelination at 21 days post injury. These results demonstrate the specific role of p38α in regulating Schwann cell myelination, and how it could be a direct therapeutic target for improving nerve repair after injury.

Keywords

Schwann, Regeneration, Repair, Peripheral nerve, Sox2, p38, Nerve injury, Demyelination, Myelin, Myelination

Document Type

Thesis

Publication Date

2016

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