TY - JOUR
T1 - MBD2 and MeCP2 regulate distinct transitions in the stage-specific differentiation of olfactory receptor neurons
AU - MacDonald, Jessica L.
AU - Verster, Adrian
AU - Berndt, Anthony
AU - Roskams, A. Jane
N1 - Funding Information:
We would like to thank Drs. Adrian Bird and Brian Hendrich (University of Edinburgh) for the Mbd2 null mice and Dr. Frank Margolis (University of Maryland) for the OMP antibody. We would also like to thank Drs. Hugh Brock and Douglas Allan for critical reading of the manuscript, Erin Currie for excellent technical assistance, Dr. Matt Lorincz for considerable help in bisulphite sequencing analysis, and Dr. Jacob Hodgson and members of the Roskams Lab for experimental insights. This work was supported by NSERC and CIHR (to J.L.M.) and the Jack Brown Family Foundation (to A.J.R.).
PY - 2010/5
Y1 - 2010/5
N2 - DNA methylation-dependent gene silencing is initiated by DNA methyltransferases (DNMTs) and mediated by methyl-binding domain proteins (MBDs), which recruit histone deacetylases (HDACs) to silence DNA, a process that is essential for normal development. Here, we show that the MBD proteins MBD2 and MeCP2 regulate distinct transitional stages of olfactory receptor neuron (ORN) differentiation in vivo. Mbd2 null progenitors display enhanced proliferation, recapitulated by HDAC inhibition, and Mbd2 null ORNs have a decreased lifespan. Mecp2 null ORNs, on the other hand, temporarily stall at the stage of terminal differentiation, retaining expression of the immature neuronal protein GAP43 after initiating expression of mature neuronal genes. The Gap43 promoter is highly methylated in the mature, but not embryonic olfactory epithelium (OE), suggesting that Gap43 may be regulated by DNA methylation during ORN differentiation. Thus, MBD2 and MeCP2 may mediate distinct, sequential transitions of ORN differentiation-an epigenetic mechanism that may be relevant to developmental regulation throughout the nervous system.
AB - DNA methylation-dependent gene silencing is initiated by DNA methyltransferases (DNMTs) and mediated by methyl-binding domain proteins (MBDs), which recruit histone deacetylases (HDACs) to silence DNA, a process that is essential for normal development. Here, we show that the MBD proteins MBD2 and MeCP2 regulate distinct transitional stages of olfactory receptor neuron (ORN) differentiation in vivo. Mbd2 null progenitors display enhanced proliferation, recapitulated by HDAC inhibition, and Mbd2 null ORNs have a decreased lifespan. Mecp2 null ORNs, on the other hand, temporarily stall at the stage of terminal differentiation, retaining expression of the immature neuronal protein GAP43 after initiating expression of mature neuronal genes. The Gap43 promoter is highly methylated in the mature, but not embryonic olfactory epithelium (OE), suggesting that Gap43 may be regulated by DNA methylation during ORN differentiation. Thus, MBD2 and MeCP2 may mediate distinct, sequential transitions of ORN differentiation-an epigenetic mechanism that may be relevant to developmental regulation throughout the nervous system.
KW - Epigenetics
KW - Histone deacetylase
KW - Neural development
KW - Neurogenesis
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U2 - 10.1016/j.mcn.2010.02.003
DO - 10.1016/j.mcn.2010.02.003
M3 - Article
C2 - 20188178
AN - SCOPUS:77950341437
SN - 1044-7431
VL - 44
SP - 55
EP - 67
JO - Molecular and Cellular Neuroscience
JF - Molecular and Cellular Neuroscience
IS - 1
ER -