Neural stem/precursor cells dynamically change their epigenetic landscape to differentially respond to BMP signaling for fate switching during brain development

Abstract

During neocortical development, tight regulation of neurogenesis-to-astrogenesis switching of neural precursor cells (NPCs) is critical to generate a balanced number of each neural cell type for proper brain functions. Accumulating evidence indicates that a complex array of epigenetic modifications and the availability of extracellular factors control the timing of neuronal and astrocytic differentiation. However, our understanding of NPC fate regulation is still far from complete. Bone morphogenetic proteins (BMPs) are renowned as cytokines that induce astrogenesis of gliogenic late-gestational NPCs. They also promote neurogenesis of mid-gestational NPCs, although the underlying mechanisms remain elusive. By performing multiple genome-wide analyses, we demonstrate that Smads, transcription factors that act downstream from BMP signaling, target dramatically different genomic regions in neurogenic and gliogenic NPCs. We found that histone H3K27 trimethylation and DNA methylation around Smad-binding sites change rapidly as gestation proceeds, strongly associated with the alteration of accessibility of Smads to their target binding sites. Furthermore, we identified two lineage-specific Smad-interacting partners—Sox11 for neurogenic and Sox8 for astrocytic differentiation—that further ensure Smad-regulated fate-specific gene induction. Our findings illuminate an exquisite regulation of NPC property change mediated by the interplay between cell-extrinsic cues and -intrinsic epigenetic programs during cortical development.

PRDM16 functions as a co-repressor in the BMP pathway to suppress neural stem cell proliferation

“…5E). A recent study reported that BMP2-induced genes are mostly enriched for neuronal and astrocyte differentiation (Katada et al, 2021), while our analysis did not identify these categories. The discrepancy may derive from difference in NSC culture, as ours was from E13 instead of E11 and E14, or different profiling methods, H3K4me3 versus RNA-seq.…”

Dephosphorylation of 4EBP1/2 Induces Prenatal Neural Stem Cell Quiescence

“…To test its use in prenatal NSC populations, neural stem cells dissected from the developing dorsal V-SVZ at embryonic day 15.5 were exposed to BMP4 with simultaneous withdrawal of EGF but maintenance of basic fibroblast growth factor (bFGF-2), and markers of cell proliferation and quiescence were quantified using fluorescence microscopy and flow cytometry. After 24 hours in media containing BMP4 and bFGF-2, levels of the proliferation marker Ki67 had significantly decreased compared to cells grown in control media containing bFGF-2 and epidermal growth factor (EGF) ( BMP4 has also been shown to direct NSCs into neuronal or astrocytic lineages depending on the time of expression (Katada et al, 2021); these effects that are directly antagonized and suppressed by EGF and FGF-2 to maintain stemness and self-renewal capacities (Lillien & Raphael, 2000;Sun et al, 2011). To ensure that the removal of EGF and exposure to BMP4 did not differentiation as reported for media containing only BMP4 without FGF-2, levels of Sox2, a transcription factor expressed by neural stem and progenitor cells, but not transit amplifying cells, were measured following acute (72 hours, Fig p-4EBP1/2 signaling decreases in embryonic NSCs following quiescence induction.…”

“…BMP4 has also been shown to direct NSCs into neuronal or astrocytic lineages depending on the time of expression (Katada et al, 2021); these effects that are directly antagonized and suppressed by EGF and FGF-2 to maintain stemness and self-renewal capacities (Lillien & Raphael, 2000; Sun et al, 2011). To ensure that the removal of EGF and exposure to BMP4 did not differentiation as reported for media containing only BMP4 without FGF-2, levels of Sox2, a transcription factor expressed by neural stem and progenitor cells, but not transit amplifying cells, were measured following acute (72 hours, Fig 2E) and prolonged (6 days, Fig 2F) exposure to BMP4.…”

Abnormal Neural Differentiation in Response to Graphene Quantum Dots through Histone Modification Interference

“…Studies have shown that the BMP signaling pathway plays different, sometimes even opposite, roles in different periods of neural differentiation [33]. The inhibition of BMP signaling is required during neural induction [34], while it plays a positive regulatory role in the formation of neural precursor cells [35]. As shown in Fig.…”