Loss of Tuberous Sclerosis Complex1 in Adult Oligodendrocyte Progenitor Cells Enhances Axon Remyelination and Increases Myelin Thickness after a Focal Demyelination

• Published in: The Journal of neuroscience 2017-08, Vol.37 (31), p.7534-7546
• Main Authors: McLane, Lauren E, Bourne, Jennifer N, Evangelou, Angelina V, Khandker, Luipa, Macklin, Wendy B, Wood, Teresa L
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Axons; Cell Differentiation - physiology; Cells (biology); Cells, Cultured; Central nervous system; Clonal deletion; Demyelinating Diseases - metabolism; Demyelinating Diseases - pathology; Demyelination; Glial stem cells; Liquid oxygen; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin; Myelin proteolipid protein; Myelin Sheath - metabolism; Myelin Sheath - pathology; Myelination; Nerve Fibers, Myelinated - metabolism; Nerve Fibers, Myelinated - pathology; Nerve Regeneration - physiology; Oligodendrocytes; Oligodendroglia - metabolism; Oligodendroglia - pathology; Progenitor cells; Proteins; Proteolipid protein; Rapamycin; Rodents; Stem Cells - metabolism; Stem Cells - pathology; TOR protein; Tuberous sclerosis; Tuberous Sclerosis Complex 1; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins - metabolism
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3454-16.2017

Although the mammalian target of rapamycin (mTOR) is an essential regulator of developmental oligodendrocyte differentiation and myelination, oligodendrocyte-specific deletion of tuberous sclerosis complex (TSC), a major upstream inhibitor of mTOR, surprisingly also leads to hypomyelination during CNS development. However, the function of TSC has not been studied in the context of remyelination. Here, we used the inducible Cre-lox system to study the function of TSC in the remyelination of a focal, lysolecithin-demyelinated lesion in adult male mice. Using two different mouse models in which is deleted by Cre expression in oligodendrocyte progenitor cells (OPCs) or in premyelinating oligodendrocytes, we reveal that deletion of affects oligodendroglia differently depending on the stage of the oligodendrocyte lineage. deletion from NG2 OPCs accelerated remyelination. Conversely, deletion from proteolipid protein (PLP)-positive oligodendrocytes slowed remyelination. Contrary to developmental myelination, there were no changes in OPC or oligodendrocyte numbers in either model. Our findings reveal a complex role for TSC in oligodendrocytes during remyelination in which the timing of deletion is a critical determinant of its effect on remyelination. Moreover, our findings suggest that TSC has different functions in developmental myelination and remyelination. Myelin loss in demyelinating disorders such as multiple sclerosis results in disability due to loss of axon conductance and axon damage. Encouragingly, the nervous system is capable of spontaneous remyelination, but this regenerative process often fails. Many chronically demyelinated lesions have oligodendrocyte progenitor cells (OPCs) within their borders. It is thus of great interest to elucidate mechanisms by which we might enhance endogenous remyelination. Here, we provide evidence that deletion of from OPCs, but not differentiating oligodendrocytes, is beneficial to remyelination. This finding contrasts with the loss of oligodendroglia and hypomyelination seen with or deletion in the oligodendrocyte lineage during CNS development and points to important differences in the regulation of developmental myelination and remyelination.