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Manipulating developmental mechanisms to promote remyelination

  • Author(s): Harrington, Emily Prentiss
  • Advisor(s): Rowitch, David H
  • et al.
Abstract

Remyelination, the ability of oligodendrocytes to extend myelin sheaths to wrap demyelinated axons, becomes progressively inefficient and can fail in multiple sclerosis (MS) leading to axonal degeneration and permanent functional deficits. Promoting remyelination and preventing axonal degeneration may improve neurological function and delay or prevent the secondary progressive phase of MS.

Many signaling pathways that regulate developmental myelination are recapitulated during remyelination. We tested whether modulation of the Akt/mTOR pathway and Wnt pathway, pathways that regulate developmental myelination, could enhance remyelination after demyelinating injury. Myelin sheaths that are formed after remyelination are thinner than myelin sheaths formed during development, and thin myelin sheaths may make axons more prone to degeneration. We tested whether activation of the Akt/mTOR pathway in oligodendrocytes, which results in developmental hypermyelination, results in thicker myelin sheaths after remyelination. We found no enhancement of myelin sheath thickness in remyelinated lesions with Akt/mTOR pathway activation and prolonged developmental hypermyelination resulted in dysmyelination and axonal degeneration of long axonal tracts.

The canonical Wnt pathway is activated in oligodendrocyte progenitors during developmental myelination and remyelination both in animal models and human neonatal white matter injury and MS. Prolonged activation of the Wnt pathway impairs oligodendrocyte differentiation and remyelination in animal models of demyelination. We wanted to determine whether inhibition of the Wnt pathway could promote remyelination and the mechanism by which the Wnt pathway inhibits differentiation. We tested whether Wnt inhibitor XAV939 could accelerate oligodendrocyte differentiation and remyelination. We found that XAV939 promoted oligodendrocyte differentiation in vitro and co-injection of XAV939 with demyelinating agent lysolecithin accelerated oligodendrocyte differentiation and remyelination in vivo. To explore the mechanism of Wnt pathway inhibition of differentiation we identified transcription factor Sp5 as a Wnt pathway target candidate that may repress mature myelin genes and inhibit differentiation. We confirmed that Sp5 is directly regulated by TCF/LEF transcription factors in oligodendrocyte progenitors. We found that Sp5 is bound to mature myelin gene promoters in oligodendrocyte progenitors but not in differentiated oligodendrocytes and Sp5 represses target gene transcription. These findings suggest that inhibiting Wnt pathway activity in demyelinated MS lesions may promote oligodendrocyte differentiation and enhance remyelination.

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