A latent lineage potential in resident neural stem cells
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ABSTRACT:
PROVIDER: PRJNA623886 | ENA |
REPOSITORIES: ENA
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Project description:Injuries to the central nervous system (CNS) are inefficiently repaired. Resident neural stem cells exist, but manifest a very limited contribution to cell replacement. Here we uncover a latent potential in neural stem cells to replace large numbers of oligodendrocytes in the injured mouse spinal cord. Using single cell genomics we found that neural stem cells are in a permissive chromatin state that enables the unfolding of a normally latent gene expression program for oligodendrogenesis after injury. Once unveiled, stem cell-derived oligodendrogenesis is abundant, follows the natural progression of oligodendrocyte differentiation, contributes to axon remyelination and stimulates functional recovery of axon conduction. Resident stem cells can thus serve as a meaningful reservoir for cellular replacement and constitute an alternative to cell transplantation after CNS injury.
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Project description:ZNF462 haploinsufficiency is linked to Weiss-Kruszka Syndrome, a genetic disorder characterized by neurodevelopmental defects including Autism. Though conserved in vertebrates and essential for embryonic development the molecular functions of ZNF462 remain unclear. We identified its murine homolog ZFP462 in a screen for mediators of epigenetic gene silencing. Here, we show that ZFP462 safeguards neural lineage specification of mouse embryonic stem cells (ESCs) by targeting the H3K9-specific histone methyltransferase complex G9A/GLP to silence mesoendodermal genes. ZFP462 binds to transposable elements (TEs) that are potential enhancers harboring ESC-specific transcription factor (TF) binding sites. Recruiting G9A/GLP, ZFP462 seeds heterochromatin, restricting TF binding. Loss of ZFP462 in ESCs results in increased chromatin accessibility at target sites and ectopic expression of mesoendodermal genes. Taken together, ZFP462 confers lineage- and locus-specificity to the broadly expressed epigenetic regulator G9A/GLP. Our results suggest that aberrant activation of lineage non-specific genes in the neuronal lineage underlies ZNF462-associated neurodevelopmental pathology.
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Project description:This SuperSeries is composed of the following subset Series: GSE33059: Sequentially acting Sox transcription factors in neural lineage development [ChIP-seq] GSE33060: Sequentially acting Sox transcription factors in neural lineage development [RNA-seq] GSE33061: Sequentially acting Sox transcription factors in neural lineage development [microarray] Refer to individual Series
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Project description:Developmental potential is progressively restricted after germ layer specification during gastrulation. However, cranial neural crest cells challenge this paradigm, as they develop from anterior ectoderm yet give rise to both mesodermal derivatives of the craniofacial skeleton and ectodermal derivatives of the peripheral nervous system. How cranial neural crest cells differentiate into multiple lineages is poorly understood. Here, we demonstrate that cranial neural crest cells possess a transient state of increased chromatin accessibility; and that the earliest premigratory neural crest are biased towards either a neuronal or ectomesenchymal fate, with each lineage expressing distinct factors from the pluripotent state. We profile the spatiotemporal emergence of each neural crest population and demonstrate that the ectomesenchymal lineage forms prior to the neuronal progenitors. Expression of the pluripotency microRNA family miR-302 is maintained in cranial neural crest cells and genetic deletion leads to precocious specification of the ectomesenchymal lineage. We find that miR-302 directly targets Sox9 to slow the timing of ectomesenchyme induction and regulates multiple genes involved in chromatin condensation to maintain accessibility for neuronal differentiation. Loss of mir-302 results in reduced chromatin accessibility in the neuronal progenitor lineage of neural crest and a reduction in peripheral neuron differentiation. Our findings reveal a post-transcriptional mechanism governed by miRNAs from pluripotency as an important mechanism to expand developmental potential of cranial neural crest.
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Project description:Developmental potential is progressively restricted after germ layer specification during gastrulation. However, cranial neural crest cells challenge this paradigm, as they develop from anterior ectoderm yet give rise to both mesodermal derivatives of the craniofacial skeleton and ectodermal derivatives of the peripheral nervous system. How cranial neural crest cells differentiate into multiple lineages is poorly understood. Here, we demonstrate that cranial neural crest cells possess a transient state of increased chromatin accessibility; and that the earliest premigratory neural crest are biased towards either a neuronal or ectomesenchymal fate, with each lineage expressing distinct factors from the pluripotent state. We profile the spatiotemporal emergence of each neural crest population and demonstrate that the ectomesenchymal lineage forms prior to the neuronal progenitors. Expression of the pluripotency microRNA family miR-302 is maintained in cranial neural crest cells and genetic deletion leads to precocious specification of the ectomesenchymal lineage. We find that miR-302 directly targets Sox9 to slow the timing of ectomesenchyme induction and regulates multiple genes involved in chromatin condensation to maintain accessibility for neuronal differentiation. Loss of mir-302 results in reduced chromatin accessibility in the neuronal progenitor lineage of neural crest and a reduction in peripheral neuron differentiation. Our findings reveal a post-transcriptional mechanism governed by miRNAs from pluripotency as an important mechanism to expand developmental potential of cranial neural crest.
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Project description:Stem cells need to balance self-renewal and differentiation for correct tissue development and homeostasis. Defects in this balance can lead to developmental defects or tumor formation. In recent years, mRNA splicing has emerged as one important mechanism regulating cell fate decisions. Here we address the role of the evolutionary conserved splicing co-factor Barricade (Barc)/CUS2/Tat-SF1 in Drosophila neural stem cell (neuroblast) lineage formation. We show that Barc is required for the generation of neurons during Drosophila brain development by ensuring correct neural progenitor proliferation and differentiation. Barc associates with components of the U2 small nuclear ribonucleic proteins (snRNP), and its depletion causes alternative splicing in form of intron retention in a subset of genes. Using bioinformatics analysis and a cell culture based splicing assay, we found that Barc dependent introns share three major traits: they are short, GC rich and have weak 3’ splice sites. Our results show that Barc, together with the U2snRNP, plays an important role in regulating neural stem cell lineage progression during brain development and facilitates correct splicing of a subset of introns.
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