Abstract
Multiple sclerosis is the most frequent demyelinating disease in the human CNS characterized by inflammation, demyelination, relative axonal loss and gliosis. Remyelination occurs, but is frequently absent or restricted to a small remyelinated rim at the lesion border. Impaired differentiation of oligodendroglial precursor cells is one factor contributing to limited remyelination, especially in chronic MS. TCF7L2 is an oligodendroglial transcription factor regulating myelin gene expression during developmental myelination as well as remyelination. TCF7L2 binds to co-effectors such as β-catenin or histone deacetylases and thereby activates or inhibits the transcription of downstream genes involved in oligodendroglial differentiation. To determine whether TCF7L2 can be used as a marker for differentiating or myelinating oligodendrocytes, we analyzed the expression patterns of TCF7L2 during myelination and remyelination in human and murine CNS tissue samples. Here, we demonstrate that marked expression of TCF7L2 in oligodendrocytes is restricted to a well defined time period during developmental myelination in human and mouse CNS tissue samples. In demyelinating diseases, such as multiple sclerosis, TCF7L2 is reexpressed in oligodendrocytes in a subset of MS patients, but is also present in tissue samples from patients with non-demyelinating, inflammatory diseases. Furthermore, TCF7L2 expression was also detected in astrocytes. HDAC2, a potential binding partner of TCF7L2 that promotes oligodendroglial differentiation and myelination, is expressed in the majority of oligodendrocytes in controls and MS tissue samples. In summary, our data demonstrate that the expression of TCF7L2 in oligodendrocytes is limited to a certain differentiation stage; however the expression of TCF7L2 is neither restricted to the oligodendroglial lineage nor to (re-)myelinating conditions.
Highlights
In Multiple sclerosis (MS) loss of axons is a prominent feature that correlates with neurological impairment [1,2,3,4]
We demonstrate that the transcription factor TCF7L2 is expressed during development and downregulated in adulthood in oligodendroglial lineage cells
The potential TCF7L2 binding partner HDAC2 is abundantly expressed in oligodendroglial lineage cells
Summary
In Multiple sclerosis (MS) loss of axons is a prominent feature that correlates with neurological impairment [1,2,3,4]. Demyelination contributes to axonal damage by increased vulnerability to immune mediated injury and lack of trophic support from myelin sheaths [7,8]. Lack of remyelination is associated with increased axonal damage and loss in demyelinating animal models and MS lesions [9,10,11]. Remyelination is a frequent event in early MS lesions, it is limited in chronic lesion stages [12,13]. About 20% of chronic MS lesions show extensive remyelination of more than 50% of the lesion area [14]. Limited remyelination despite the presence of OPCs in the majority of chronic MS lesions suggests that a differentiation block of oligodendrocytes contributes to remyelination failure [15,16,17]
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