Neural stem cell transcriptional networks highlight genes essential for nervous system development.
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ABSTRACT:
SUBMITTER: Southall TD
PROVIDER: S-EPMC2770102 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Alternative splicing (AS) generates vast transcriptomic complexity in the vertebrate nervous system. However, the extent to which trans-acting splicing regulators and their target AS regulatory networks contribute to nervous system development is not completely understood. To address these questions, we have generated mice lacking the vertebrate- and neural-specific Ser/Arg-repeat related protein of 100 kDa (nSR100/SRRM4). Loss of nSR100 impairs development of the central and peripheral nervous systems, in part by disrupting neurite outgrowth, cortical layering in the forebrain, and axon guidance in the corpus callosum. Accompanying these developmental defects are widespread changes in AS that primarily result in shifts to non-neural patterns for different classes of splicing events. The main component of the altered AS program comprises 3-27 nucleotide neural microexons, an emerging class of highly conserved alternative splicing event associated with the regulation of protein interaction networks in developing neurons and neurological disorders. Remarkably, inclusion of a 6-nucleotide nSR100-activated microexon in Unc13b transcripts is sufficient to rescue a neuritogenesis defect in nSR100 mutant primary neurons. These results thus reveal critical in vivo neurodevelopmental functions of nSR100, and they further link these functions to a conserved program of neural microexon splicing. mRNA profiles of mouse control or nSR100/Srrm4 KO cortex or hippocampus using high-throughput sequencing data.
2015-04-14 | E-GEOD-65818 | biostudies-arrayexpress
Project description:The maintenance of pluripotency and specification of cellular lineages during embryonic development are controlled by transcriptional regulatory networks, which coordinate specific sets of genes through both activation and repression. The transcriptional repressor RE1-silencing transcription factor (REST) plays important but distinct regulatory roles in embryonic (ESC) and neural (NSC) stem cells. We investigated how these distinct biological roles are effected at a genomic level. We present integrated, comparative genome- and transcriptome-wide analyses of transcriptional networks governed by REST in mouse ESC and NSC. The REST recruitment profile has dual components: a developmentally independent core that is common to ESC, NSC, and differentiated cells; and a large, ESC-specific set of target genes. In ESC, the REST regulatory network is highly integrated into that of pluripotency factors Oct4-Sox2-Nanog. We propose that an extensive, pluripotency-specific recruitment profile lends REST a key role in the maintenance of the ESC phenotype.
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Project description:BACKGROUND:Mov10 is an RNA helicase that modulates access of Argonaute 2 to microRNA recognition elements in mRNAs. We examined the role of Mov10 in Xenopus laevis development and show a critical role for Mov10 in gastrulation and in the development of the central nervous system (CNS). RESULTS:Knockdown of maternal Mov10 in Xenopus embryos using a translation blocking morpholino led to defects in gastrulation and the development of notochord and paraxial mesoderm, and a failure to neurulate. RNA sequencing of the Mov10 knockdown embryos showed significant upregulation of many mRNAs when compared with controls at stage 10.5 (including those related to the cytoskeleton, adhesion, and extracellular matrix, which are involved in those morphogenetic processes). Additionally, the degradation of the miR-427 target mRNA, cyclin A1, was delayed in the Mov10 knockdowns. These defects suggest that Mov10's role in miRNA-mediated regulation of the maternal to zygotic transition could lead to pleiotropic effects that cause the gastrulation defects. Additionally, the knockdown of zygotic Mov10 showed that it was necessary for normal head, eye, and brain development in Xenopus consistent with a recent study in the mouse. CONCLUSIONS:Mov10 is essential for gastrulation and normal CNS development. Developmental Dynamics 247:660-671, 2018. © 2017 Wiley Periodicals, Inc.
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Project description:Alternative splicing (AS) generates vast transcriptomic complexity in the vertebrate nervous system. However, the extent to which trans-acting splicing regulators and their target AS regulatory networks contribute to nervous system development is not well understood. To address these questions, we generated mice lacking the vertebrate- and neural-specific Ser/Arg repeat-related protein of 100 kDa (nSR100/SRRM4). Loss of nSR100 impairs development of the central and peripheral nervous systems in part by disrupting neurite outgrowth, cortical layering in the forebrain, and axon guidance in the corpus callosum. Accompanying these developmental defects are widespread changes in AS that primarily result in shifts to nonneural patterns for different classes of splicing events. The main component of the altered AS program comprises 3- to 27-nucleotide (nt) neural microexons, an emerging class of highly conserved AS events associated with the regulation of protein interaction networks in developing neurons and neurological disorders. Remarkably, inclusion of a 6-nt, nSR100-activated microexon in Unc13b transcripts is sufficient to rescue a neuritogenesis defect in nSR100 mutant primary neurons. These results thus reveal critical in vivo neurodevelopmental functions of nSR100 and further link these functions to a conserved program of neuronal microexon splicing.
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Project description:BackgroundThe transcriptional regulatory network is considered to be built from a set of circuit patterns called network motifs. Experimental studies have provided instances where a feedforward circuit (FFC) appears with modification of autoregulation, but little is known systematically about such autoregulation-integrated FFCs. Therefore, we aimed to examine whether the autoregulation-integrated FFC is a network motif relevant to describing the human transcriptional regulatory systems, and explored the relationship of such network motifs with biological functions.ResultsBased on human-mouse evolutionarily conserved transcription factor binding sites (TFBSs) in 76600 conserved blocks for 5169 genes, we compiled the human transcriptional connections into a matrix, and examined the number of FFC appearances in comparison with randomized networks. The results revealed that the configuration of autoregulation integrated in the FFC critically affects the abundance or avoidance of FFC appearances. In particular, an FFC comprising two repressors that are both autoregulated was revealed as a significant network motif, which we termed the double-autoregulation FFC (DAR-FFC). Interestingly, this network motif preferentially constitutes effecter transcriptional circuits with functions in cell-cell signaling and multicellular organization, and is particularly related to nervous system development.ConclusionsWe have revealed that the configuration of autoregulation integrated in the FFCs is a critical factor for abundance or avoidance of the appearance of the FFCs. In particular, we have identified the DAR-FFC as a distinctive integrated network motif endowed with properties that are indispensable for forming the transcriptional regulatory circuits involved in multicellular organization and nervous system development. This is the first report showing that the DAR-FFC is a significant network motif.
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Project description:During neurogenesis, transcription factors combinatorially specify neuronal fates and then differentiate subtype identities by inducing subtype-specific gene expression profiles. But how is neuronal subtype identity maintained in mature neurons? Modeling this question in two Drosophila neuronal subtypes (Tv1 and Tv4), we test whether the subtype transcription factor networks that direct differentiation during development are required persistently for long-term maintenance of subtype identity. By conditional transcription factor knockdown in adult Tv neurons after normal development, we find that most transcription factors within the Tv1/Tv4 subtype transcription networks are indeed required to maintain Tv1/Tv4 subtype-specific gene expression in adults. Thus, gene expression profiles are not simply "locked-in," but must be actively maintained by persistent developmental transcription factor networks. We also examined the cross-regulatory relationships between all transcription factors that persisted in adult Tv1/Tv4 neurons. We show that certain critical cross-regulatory relationships that had existed between these transcription factors during development were no longer present in the mature adult neuron. This points to key differences between developmental and maintenance transcriptional regulatory networks in individual neurons. Together, our results provide novel insight showing that the maintenance of subtype identity is an active process underpinned by persistently active, combinatorially-acting, developmental transcription factors. These findings have implications for understanding the maintenance of all long-lived cell types and the functional degeneration of neurons in the aging brain.
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Project description:Alternative splicing (AS) generates vast transcriptomic complexity in the vertebrate nervous system. However, the extent to which trans-acting splicing regulators and their target AS regulatory networks contribute to nervous system development is not completely understood. To address these questions, we have generated mice lacking the vertebrate- and neural-specific Ser/Arg-repeat related protein of 100 kDa (nSR100/SRRM4). Loss of nSR100 impairs development of the central and peripheral nervous systems, in part by disrupting neurite outgrowth, cortical layering in the forebrain, and axon guidance in the corpus callosum. Accompanying these developmental defects are widespread changes in AS that primarily result in shifts to non-neural patterns for different classes of splicing events. The main component of the altered AS program comprises 3-27 nucleotide neural microexons, an emerging class of highly conserved alternative splicing event associated with the regulation of protein interaction networks in developing neurons and neurological disorders. Remarkably, inclusion of a 6-nucleotide nSR100-activated microexon in Unc13b transcripts is sufficient to rescue a neuritogenesis defect in nSR100 mutant primary neurons. These results thus reveal critical in vivo neurodevelopmental functions of nSR100, and they further link these functions to a conserved program of neural microexon splicing.
2015-04-14 | GSE65818 | GEO
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