MBD2 and MeCP2 regulate distinct transitions in the stage-specific differentiation of olfactory receptor neurons

Mol Cell Neurosci. 2010 May;44(1):55-67. doi: 10.1016/j.mcn.2010.02.003. Epub 2010 Feb 24.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics*
  • Cell Proliferation
  • DNA Methylation / physiology
  • DNA-Binding Proteins / genetics*
  • Epigenesis, Genetic / genetics
  • GAP-43 Protein / genetics
  • GAP-43 Protein / metabolism
  • Gene Expression Regulation, Developmental / genetics
  • Gene Silencing / physiology
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Male
  • Methyl-CpG-Binding Protein 2 / genetics*
  • Mice
  • Mice, Knockout
  • Neurogenesis / physiology
  • Olfactory Mucosa / cytology
  • Olfactory Mucosa / embryology*
  • Olfactory Mucosa / growth & development*
  • Olfactory Receptor Neurons / cytology
  • Olfactory Receptor Neurons / metabolism*
  • Promoter Regions, Genetic / genetics

Substances

  • DNA-Binding Proteins
  • GAP-43 Protein
  • Mbd2 protein, mouse
  • Methyl-CpG-Binding Protein 2
  • Histone Deacetylases