Polycomb Limits the Neurogenic Competence of Neural Precursor Cells to Promote Astrogenic Fate Transition

Abstract

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.

Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex

“…The findings reported here contrast with a recent report of the consequences of deletion of Ring1B (PRC1) and of Ezh2 in the E12 cortex during the neurogenic period (21). Deletion of Ring1B at that stage results in a phenotype opposite that reported here: The neurogenic period is extended, and gliogenesis is delayed (21).…”

“…Deletion of Ring1B at that stage results in a phenotype opposite that reported here: The neurogenic period is extended, and gliogenesis is delayed (21). From the brief description provided in that work, it appears that a similar phenotype was observed when Ezh2 was deleted at the same developmental stage (21).…”

“…Furthermore, removal of Ring1B, an ubiquitin ligase component of PRC1, from the developing cortex during neurogenesis lengthens the period of neurogenesis and delays the onset of gliogenesis (21). Deletion of Ezh2 at the same developmental stage appears to produce the same phenotype (21). We report here that deletion of the histone methyltransferase of PRC2, Ezh2, in mouse cortical progenitor cells before the onset of neurogenesis changes the balance between differentiation and selfrenewal, significantly altering developmental timing in this system.…”

“…However, acute deletion of Bmi1 by RNAi does compromise cortical progenitor cell self-renewal (20). Furthermore, removal of Ring1B, an ubiquitin ligase component of PRC1, from the developing cortex during neurogenesis lengthens the period of neurogenesis and delays the onset of gliogenesis (21). Deletion of Ezh2 at the same developmental stage appears to produce the same phenotype (21).…”

Histone demethylase Jmjd3 is required for the development of subsets of retinal bipolar cells

“…Dynamic switches in polycomb targets that restrict pluripotency and define the developmental potential of progenitor cells have been demonstrated by differentiation of ES cells into Pax6-positive radial-glial neuronal progenitor cells (7). The role of H3K27 in defining the timing of neurogenesis and gliogenesis was shown in cortical neurons by ablating Ezh2 at different developmental stages (8)(9)(10). Jmjd3 (Kdm6b) and Utx (Kdm6a) are H3K27 demethylases (11,12).…”