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[P150]: Elucidation of neuron‐derived feedback signals that regulate oligodendrocyte genesis
Author(s) -
Paquin A.,
Wasylnka J.,
Kaplan D.,
Miller F.
Publication year - 2006
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/j.ijdevneu.2006.09.211
Subject(s) - miller , sick child , citation , psychology , library science , medicine , pediatrics , computer science , biology , ecology
Sox2 plays a key role in neurodevelopment. It is involved in the maintenance of pluripotency in ES and its function is essential in neural stem cells. In the developing neocortex, Sox2 expression is restricted to the actively proliferating cell populations (i.e., neural stem and progenitor cells, glial precursors and astrocytes) and its function interferes with the terminal differentiation of neurons, but not astrocytes. The gene is silenced in the post-mitotic neurons, but it continues to be expressed in mitotically-active astrocytes until they become quiescent. Yet, signals capable of astrocytic activation (i.e., injury, mitogenic and gliogenic factors) can trigger Sox2 re-expression (BaniYaghoub et al., 2006). Therefore, Sox2 is an ideal gene to study the role of epigenetic mechanisms in control of key developmental processes in the brain. Two enhancers, SRR1 and SRR2, located 4 kb upstream and 4 kb downstream of the Sox2 coding region, respectively, have been shown to be responsible for Sox2 expression during development of the telencephalon and the cortex. Here, we show that these enhancers are subject to dynamic changes in DNA methylation and histone H3 acetylation during the differentiation of human NT2/D1 EC cells into astrocytes and neurons in response to retinoic acid. In undifferentiated EC cells, where the gene is expressed at high levels, the DNA of both enhancers was unmethylated and associated with acetylated histone H3. By contrast, in neurons, where the gene is silenced, both enhancers were methylated and histones deacetylated. In quiescent astrocytes, on the other hand, where Sox2 is also turned off, only the SRR1 enhancer, but not the SRR2, was methylated. Significantly, this lack of SRR2 methylation seemed essential for astrocytes to re-activate Sox2 expression. Indeed, stimulation of quiescent astrocytes with bFGF triggered the re-expression of the gene. This was preceeded by transient de-methylation of SRR1 and increases in histone acetylation at both SRR1 and SRR2 enhancers. As Sox2 activity declined, the epigenetic marks were re-established again. Taken together, it is evident that epigenetic mechanisms play a major role in the regulation of Sox2 expression and, thus, its function during neurodevelopment.