MBD2 and MeCP2 regulate distinct transitions in the stage-specific differentiation of olfactory receptor neurons.
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.
Macdonald
Jessica L
JL
Department of Zoology, Life Sciences Institute and Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
Verster
Adrian
A
Berndt
Anthony
A
Roskams
A Jane
AJ
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D019175:DNA Methylation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics; D019922:GAP-43 Protein / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D020868:Gene Silencing / Q000502:physiology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology; D009831:Olfactory Mucosa / Q000166:cytology / Q000196:embryology* / Q000254:growth & development*; D018034:Olfactory Receptor Neurons / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics
D004268:DNA-Binding Proteins; D019922:GAP-43 Protein; C489326:Mbd2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D006655:Histone Deacetylases