Abstract
Demyelination is the cause of disability in various neurological disorders. It is therefore crucial to understand the molecular regulation of oligodendrocytes, the myelin forming cells in the CNS. Growth factors are known to be essential for the development and maintenance of oligodendrocytes and are involved in the regulation of glial responses in various pathological conditions. We employed the well established murine cuprizone model of toxic demyelination to analyze the expression of 13 growth factors in the CNS during de- and remyelination. The temporal mRNA expression profile during demyelination and the subsequent remyelination were analyzed separately in the corpus callosum and cerebral cortex using laser microdissection and real-time PCR techniques. During demyelination a similar pattern of growth factor mRNA expression was observed in both areas with a strong up-regulation of NRG1 and GDNF and a slight increase of CNTF in the first week of cuprizone treatment. HGF, FGF-2, LIF, IGF-I, and TGF-ß1 were up-regulated mainly during peak demyelination. In contrast, during remyelination there were regional differences in growth factor mRNA expression levels. GDNF, CNTF, HGF, FGF-2, and BDNF were elevated in the corpus callosum but not in the cortex, suggesting tissue differences in the molecular regulation of remyelination in the white and grey matter. To clarify the cellular source we isolated microglia from the cuprizone lesions. GDNF, IGF-1, and FGF mRNA were detected in the microglial fraction with a temporal pattern corresponding to that from whole tissue PCR. In addition, immunohistochemical analysis revealed IGF-1 protein expression also in the reactive astrocytes. CNTF was located in astrocytes. This study identified seven different temporal expression patterns for growth factors in white and grey matter and demonstrated the importance of early tissue priming and exact orchestration of different steps during callosal and cortical de- and remyelination.
Highlights
In demyelinating diseases of the central nervous system (CNS) like multiple sclerosis (MS) and the leukodystrophies, repair mechanisms and remyelination fail leading to neurological impairment
The mRNA expression of myelin basic protein (MBP) and proteolipid protein (PLP) was strongly decreased after one week and remained down-regulated during the whole cuprizone feeding (Fig. 1I, J)
Growth factors are involved in the orchestration of proliferation, migration, and differentiation of glial cells in demyelinating diseases and are suggested to support remyelination in the CNS
Summary
In demyelinating diseases of the central nervous system (CNS) like multiple sclerosis (MS) and the leukodystrophies, repair mechanisms and remyelination fail leading to neurological impairment. Regenerative therapies in these diseases are currently not available, the understanding of the molecular events during de- and remyelination is necessary to develop new treatment strategies. Neurotrophins, neuropoietic cytokines, and other growth factors are suggested to support migration, proliferation, and differentiation of glial cells and to regulate myelin synthesis [3,4,5]. A disturbed balance of interacting GFs that regulate differentiation of oligodendrocytes and onset of myelination may contribute to the limited remyelination of MS plaques [6,7]. Knowledge of the exact regulation and requirements for GF expression during remyelination may allow the design of specific regenerative treatments for demyelinating diseases
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