| Abstract No.: | C-A3021 |
| Country: | Canada |
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| Title: | MBD2 AND MECP2 REGULATE DIFFERENT TRANSITIONS IN THE STAGE-SPECIFIC DIFFERENTIATION OF OLFACTORY RECEPTOR NEURONS |
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| Authors/Affiliations: | 2 Jessica L. MacDonald*; 1 A. Jane Roskams;
1 University of British Columbia, Department of Zoology, Vancouver, BC, Canada; 2 University of British Columbia, Graduate Program in Neuroscience, Department of Zoology, Vancouver, BC, Canada
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| Content: | Methylation of cytosine residues is associated with epigenetic gene silencing and is critical for mammalian development. DNA methylation-dependent chromatin remodelling is initiated by DNA methyltransferases (DNMTs), and mediated by methyl-binding domain proteins (MBDs), which recruit histone deacetylases (HDACs) to silence DNA Disruptions in this process have been implicated in neurodevelopmental disorders, including Rett Syndrome. Neurogenesis of olfactory receptor neurons (ORNs) continues throughout the lifetime in the rodent olfactory epithelium, providing us an accessible, non-embryonic tissue in which to study DNA methylation-dependent gene silencing during neuronal differentiation. We have shown previously that the de novo DNMTs (3a and 3b) are expressed in a stage-specific, sequential pattern during olfactory neurogenesis. Although this sequence of events is essential for mammalian development, relatively little is known about the role of DNA methylation-dependent gene silencing in nervous system development. Here, we show that MBD2 and MeCP2 are expressed at sequential stages in ORN differentiation, and associate with different combinations of HDACs. MeCP2 is induced in terminally differentiating ORNs, and its absence delays ORN terminal differentiation, resulting in an accumulation of immature ORNs that demonstrate mixed expression of mature and immature proteins. In contrast, MBD2b is expressed in proliferating neural progenitors, whereas MBD2a is restricted to mature ORNs. ORNs that develop in the absence of MBD2 demonstrate decreased survival, and their adult progenitors exhibit aberrant proliferation kinetics. Enhanced progenitor proliferation occurs in Mbd2 nulls suggests that MBD2 regulates the shift from mitotic precursor to committed neuroblast. This dysregulation of progenitor cell cycle exit is also seen when HDACs are acutely inhibited with valproic acid in vivo. These results indicate that different MBD proteins mediate distinct, sequential transitional stages of ORN differentiation - an epigenetic mechanism that may be widely relevant to developmental regulation throughout the nervous system.
Funding was provided by NSERC and CIHR (to JM)
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