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Tissue-wide Genetic and Cellular Landscape Instructs the Execution of Sequential PRC2 Functions in Neural Stem Cell Lineage Progression [neurons]

ABSTRACT: The generation of a correctly-sized cerebral cortex with all-embracing neuronal and glial cell-type diversity critically depends on faithful radial glial progenitor (RGP) cell proliferation/differentiation programs. Temporal RGP lineage progression is regulated by Polycomb Repressive Complex 2 (PRC2) and loss of PRC2 activity results in severe neurogenesis defects and microcephaly. How PRC2-dependent gene expression instructs RGP lineage progression is unknown. Here we utilize Mosaic Analysis with Double Markers (MADM)-based single cell technology and demonstrate that PRC2 is not cell-autonomously required in neurogenic RGPs but rather acts at the global tissue-wide level. Conversely, cortical astrocyte production and maturation is cell-autonomously controlled by PRC2-dependent transcriptional regulation. We thus reveal highly distinct and sequential PRC2 functions in RGP lineage progression that are dependent on complex interplays between intrinsic and tissue-wide mechanisms. In a broader context our results imply a critical role for the genetic and cellular niche environment in neural stem cell behavior.

ORGANISM(S): Mus musculus

PROVIDER: GSE191108 | GEO | 2022/09/12

REPOSITORIES: GEO

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Tissue-wide Genetic and Cellular Landscape Instructs the Execution of Sequential PRC2 Functions in Neural Stem Cell Lineage Progression [astro]

Project description:The generation of a correctly-sized cerebral cortex with all-embracing neuronal and glial cell-type diversity critically depends on faithful radial glial progenitor (RGP) cell proliferation/differentiation programs. Temporal RGP lineage progression is regulated by Polycomb Repressive Complex 2 (PRC2) and loss of PRC2 activity results in severe neurogenesis defects and microcephaly. How PRC2-dependent gene expression instructs RGP lineage progression is unknown. Here we utilize Mosaic Analysis with Double Markers (MADM)-based single cell technology and demonstrate that PRC2 is not cell-autonomously required in neurogenic RGPs but rather acts at the global tissue-wide level. Conversely, cortical astrocyte production and maturation is cell-autonomously controlled by PRC2-dependent transcriptional regulation. We thus reveal highly distinct and sequential PRC2 functions in RGP lineage progression that are dependent on complex interplays between intrinsic and tissue-wide mechanisms. In a broader context our results imply a critical role for the genetic and cellular niche environment in neural stem cell behavior.

2022-09-12 | GSE191107 | GEO

Metabolic lactate production coordinates vasculature development and progenitor behavior in the developing mouse neocortex

Project description:Proper neural progenitor behavior in conjunction with orderly vasculature formation is fundamental to the development of the neocortex. However, the mechanisms coordinating neural progenitor behavior and vessel growth remain largely elusive. Here we show that robust metabolic production of lactate by radial glial progenitors (RGPs) co-regulates vascular development and RGP division behavior in the developing mouse neocortex. RGPs undergo a highly organized lineage progression program to produce diverse neural progeny. Systematic single cell metabolic state analysis revealed that RGPs and their progeny exhibit distinct metabolic features associated with specific cell types and lineage progression statuses. Symmetrically dividing, proliferative RGPs preferentially express a cohort of genes that support glucose uptake and anaerobic glycolysis. Consequently, they consume glucose in anaerobic metabolism and produce a high level of lactate, which promotes vessel growth. Moreover, lactate production enhances RGP proliferation by maintaining mitochondrial length. Together, these results suggest that specific metabolic states and metabolites coordinately regulate vasculature formation and progenitor behavior in neocortical development.

2022-06-06 | GSE201991 | GEO

A brain precursor atlas reveals the acquisition of developmental-like states in adult cerebral tumours

Project description:We map the development of mouse cerebrum across the developmental time-course, from embryonic day 12.5 to postnatal day 365, performing single-cell transcriptomics on >100,000 cells. By comparing this reference atlas to single-cell data from >100 glial tumours of the adult and pediatric human cerebrum, we find that tumour cells have an expression signature that overlaps with temporally restricted, embryonic radial glial precursors (RGPs) and their immediate sublineages. Further, we demonstrate that transformation of early RGPs in a genetic mouse model gives rise to adult cerebral tumours that show an embryonic/juvenile RGP identity. Together, these findings implicate the acquisition of embryonic-like states in the genesis of adult glioma, providing insight into the origins of human glioma, and identifying specific developmental cell types for therapeutic targeting.

2022-06-14 | GSE200202 | GEO

Multipotent Progenitors Instruct Ontogeny of the Superior Colliculus - pooled embryonic Fzd10 lineage

Project description:The superior colliculus (SC) in the mammalian midbrain is essential for multisensory integration and is composed of a rich diversity of excitatory and inhibitory neurons and glia. The developmental principles directing the generation of SC cell-type diversity are however not understood. Here we pursued systematic cell lineage tracing in silico and in vivo, preserving full spatial information, using genetic MADM (Mosaic Analysis with Double Markers)-based clonal analysis with single-cell sequencing (MADM-CloneSeq). The analysis of clonally-related cell lineages revealed that radial glial progenitor (RGP) cells in SC are exceptionally multipotent. Individual resident RGPs have the capacity to produce all excitatory and inhibitory SC neuron types, even at the stage of terminal division. While individual clonal units show no pre-defined cellular composition, the establishment of appropriate relative proportions of distinct neuronal types occurs in a PTEN-dependent manner. Collectively, our findings provide an inaugural framework at single RGP/cell level of the mammalian SC ontogeny

2023-11-03 | GSE245105 | GEO

Multipotent Progenitors Instruct Ontogeny of the Superior Colliculus – Pten

2023-11-03 | GSE245104 | GEO

Multipotent Progenitors Instruct Ontogeny of the Superior Colliculus – MADM-CloneSeq E12

2023-11-03 | GSE245103 | GEO

Multipotent Progenitors Instruct Ontogeny of the Superior Colliculus – MADM-CloneSeq E10

2023-11-03 | GSE245102 | GEO

Gene profiles regulated and targeted by PRC2 in oligodendrocyte lineage cells

Project description:The PRC2 complex creates a repressive mark histone-H3-Lys27-trimethylation. Although PRC2 is involved in various biological processes, its role in glial development remains ambiguous. We find PRC2 complex is required for oligodendrocyte (OL) differentiation and myelination, but not for OL precursor formation. Furthermore, most PRC2-null OL lineage cells (cKO) acquire astrocyte features. RNA profiles from RNAseq assay reveal that many transcription factors involved in oligodendrocyte and astrocyte development are regulated by PRC2. Moreover, PRC2-null OL lineage cells aberrantly induce Notch-NFIA and Wnt pathway genes. The chromatin immunoprecipitation-sequencing (ChIPseq) assay further reveals that PRC2 is recruited to many of Notch-NFIA and Wnt pathway genes. The datasets demonstrate the molecular program underlying the specific action of PRC2 and suggest PRC2 as a gatekeeper that determines the timing of OL lineage progression and myelination.

2020-09-15 | GSE130628 | GEO

Transcriptomic profile in the fetal cerebral cortex after maternal sevoflurane

Project description:It has been reported that 0.75-2% of pregnant women undergo non-obstetric surgeries in the first two trimester which is the period for neurogenesis. Radial glial progenitors (RGPs) give rise to most if not all pyramidal neurons in embryonic brains. Here, we evaluated the acute alterations in RGPs after maternal sevoflurane exposure by analyzing transcriptomic profile.

2021-04-15 | GSE166607 | GEO

Genome-wide promoter methylation analysis associated with malignant melanoma progression

Project description:Epigenetic alterations play significant roles in the melanoma tumorigenesis and malignant progression. We profiled genome-wide promoter DNA methylation patterns of melanoma cells deribed from primary lesions of Radial Growrth phase (RGP) and Vertical Growth Phase (VGP), metastatic lesions, and primary normal melanocytes by interrogating 14,495 genes using Illumina bead chip technology. By comparative analysis of the promoter methylation profiles, we identified epigenetically silenced gene signatures that potentially associated with malignant melanoma progression. Bisulphite converted genomic DNA from a group of melanoma cells representing pathologic stages of melanoma progression (3 cell lines derived from RGP melanoma lesions, 4 cell lines derived from VGP lesions, and 3 melastatic melanomas) and normal human primary melanocytes isolated from lightly pigmented adult skin were hybridized to Illumina's Infinium HumanMethylation27 BeadChips

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