Maintenance of Undifferentiated State and Self-Renewal of Embryonic Neural Stem Cells by Polycomb Protein Ring1B

Abstract

Cell lineages generated during development and tissue maintenance are derived from self-renewing stem cells by differentiation of their committed progeny. Recent studies suggest that epigenetic mechanisms, and in particular the Polycomb group (PcG) of genes, play important roles in controlling stem cell self-renewal. Here, we address PcG regulation of stem cell self-renewal and differentiation through inactivation of Ring1B, a histone H2A E3 monoubiquitin ligase, in embryonic neural stem cells (NSCs) from the olfactory bulb of a conditional mouse mutant line. We show that neural stem/progenitor cell proliferation in vivo and in neurosphere assays is impaired, lacking Ring1B, and their selfrenewal and multipotential abilities, assessed as sphere formation and differentiation from single cells, are severely affected. We also observed unscheduled neuronal, but not glial, differentiation of mutant stem/progenitor cells under proliferating conditions, an alteration enhanced in cells also lacking Ring1A, the Ring1B paralog, some of which turned into morphologically identifiable neurons. mRNA analysis of mutant cells showed upregulation of some neuronal differentiation-related transcription factors and the cell proliferation inhibitor Cdkn1a/p21, as well as downregulation of effectors of the Notch signaling pathway, a known inhibitor of neuronal differentiation of stem/progenitor cells. In addition, differentiation studies of Ring1B-deficient progenitors showed decreased oligodendrocyte formation in vitro and enhanced neurogenesis and reduced gliogenesis in vivo. These data suggest a role for Ring1B in maintenance of the undifferentiated state of embryonic neural stem/progenitor cells. They also suggest that Ring1B may modulate the differentiation potential of NSCs to neurons and glia. STEM

The Polycomb Repressive Complex 1 Protein BMI1 Is Required for Constitutive Heterochromatin Formation and Silencing in Mammalian Somatic Cells

“…Furthermore, there was no apparent effect on H2A ub levels at heterochromatin. This finding leaves us open with many explanations, one being functional compensation by RING1A for H2A ub deposition, as shown in other context (50,(63)(64)(65). It is also possible that in addition to promote H2A ub at silenced developmental genes and heterochromatin, BMI1 stimulates chromatin compaction and H3K9 me3 loading through interactions and activities not shared by RING1A or RING1B (66).…”

Polycomb complexes in stem cells and embryonic development

“…Interestingly, the PRC1 component Bmi1 has been reported to control the proliferation of neural progenitors by repressing p21 (Cdkn1a) (Fasano et al, 2007;Román-Trufero et al, 2009) and the Ink4/Arf cell cycle inhibitory proteins p16 (Cdkn2a) and p19 (Cdkn2d) (Molofsky et al, 2003; Bruggeman et al, 2005).…”

Switch-Like Roles for Polycomb Proteins from Neurodevelopment to Neurodegeneration

“…To address a potential role for PcG mediated ubiquitination in NSCs, Román-Trufero et al [88] inactivated Ring1B in embryonic NSCs from the olfactory bulb. This led to an impaired neural stem/progenitor cell proliferation, with single cells showing a premature neuronal differentiation in vitro; an effect that was further enhanced by the simultaneous deletion of Ring1A.…”