| Oligodendrocytes are myelin-forming cells that insulate and provide metabolic support to neurons, enabling the proper function of the central nervous system. They differentiate from progenitor cells in response to biochemical, electrical and mechanical signals. The differentiation process involves molecular and morphological changes, including the progressive formation of heterochromatin and its localization at the nuclear periphery. In chapter I of this thesis I review the different stages of oligodendrocyte differentiation and myelination, and the molecular mechanisms involved in these events. Research carried out by our laboratory and other groups has emphasized the role of repressive epigenetic mechanisms in favoring oligodendrocyte differentiation. However, the molecular mechanisms responsible for the localization of nuclear heterochromatin and its functional role in myelin biology have not been addressed. Chapter II of this thesis focuses on these questions, where we provide evidence in support of Lamin A/C as critical for oligodendrocyte nuclear organization and myelin function. By using silencing and genetic ablation approaches, we show that Lamin A/C is a nuclear scaffold protein that is necessary for heterochromatin formation at the nuclear periphery during differentiation. We further characterize an age-dependent myelin phenotype in Lmna -/- mice and define the associated transcriptional changes. We conclude that Lamin A/C is part of the mechanism responsible for myelin maintenance. In chapter III, we report the effect of mechanical forces on oligodendrocyte differentiation and show that mechanostimulation modifies the actin cytoskeleton and through the interaction with components of the LINC complex (e.g. Syne), modulates the deposition of repressive histone marks and of heterochromatin. The expression levels of LINC components increase during oligodendrocyte differentiation, and silencing the Syne1 gene results in aberrant histone mark deposition, chromatin reorganization, and impaired myelination. We conclude that spatial constraints, via the actin cytoskeleton and LINC complex, mediate nuclear changes in oligodendrocyte progenitors that favor a default pathway of differentiation. |
