ABSTRACT
In the developing neocortex, neural precursor cells (NPCs) sequentially generate various neuronal subtypes in a defined order. Although the precise timing of the NPC fate switches is essential for determining the number of neurons of each subtype and for precisely generating the cortical layer structure, the molecular mechanisms underlying these switches are largely unknown. Here, we show that epigenetic regulation through Ring1B, an essential component of polycomb group (PcG) complex proteins, plays a key role in terminating NPC-mediated production of subcerebral projection neurons (SCPNs). The level of histone H3 residue K27 trimethylation at and Ring1B binding to the promoter of Fezf2, a fate determinant of SCPNs, increased in NPCs as Fezf2 expression decreased. Moreover, deletion of Ring1B in NPCs, but not in postmitotic neurons, prolonged the expression of Fezf2 and the generation of SCPNs that were positive for CTIP2. These results indicate that Ring1B mediates the timed termination of Fezf2 expression and thereby regulates the number of SCPNs.
Subject(s)
Epigenesis, Genetic/physiology , Gene Expression Regulation, Developmental/physiology , Neocortex/embryology , Neurogenesis/physiology , Neurons/physiology , Polycomb Repressive Complex 1/metabolism , Ubiquitin-Protein Ligases/metabolism , Animals , Bromodeoxyuridine , Chromatin Immunoprecipitation , DNA-Binding Proteins/metabolism , Flow Cytometry , Gene Expression Regulation, Developmental/genetics , Immunohistochemistry , Mice , Nerve Tissue Proteins/metabolism , Neurogenesis/genetics , Neurons/cytology , RNA, Small Interfering/genetics , Repressor Proteins/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tumor Suppressor Proteins/metabolismABSTRACT
During neocortical development, neural precursor cells (NPCs, or neural stem cells) produce neurons first and astrocytes later. Although the timing of the fate switch from neurogenic to astrogenic is critical for determining the number of neurons, the mechanisms are not fully understood. Here, we show that the polycomb group complex (PcG) restricts neurogenic competence of NPCs and promotes the transition of NPC fate from neurogenic to astrogenic. Inactivation of PcG by knockout of the Ring1B or Ezh2 gene or Eed knockdown prolonged the neurogenic phase of NPCs and delayed the onset of the astrogenic phase. Moreover, PcG was found to repress the promoter of the proneural gene neurogenin1 in a developmental-stage-dependent manner. These results demonstrate a role of PcG: the temporal regulation of NPC fate.
