Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA387009 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5573020.fastq.gz | Fastqsanger.gz | |||
| SRR5573021.fastq.gz | Fastqsanger.gz | |||
| SRR5573022.fastq.gz | Fastqsanger.gz | |||
| SRR5573023.fastq.gz | Fastqsanger.gz | |||
| SRR5573024.fastq.gz | Fastqsanger.gz |
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Project description:N6-methyladenosine (m6A), installed by the Mettl3/Mettl14 methyltransferase complex, is the most prevalent internal mRNA modification. Whether m6A regulates mammalian brain development is unknown. Here we show that Mettl14 deletion in the embryonic mouse brain diminishes m6A levels, prolongs cell cycle of radial glia cells, and extends cortical neurogenesis into postnatal stages. Mettl3 knockdown also prolongs neural progenitor cell cycle and promotes radial glia cell maintenance. m6A-sequencing of the embryonic mouse cortex reveals enrichment of mRNAs related to transcription factors, cell cycle and neuron differentiation, and Mettl14 deletion attenuates their decay. Notably, Mettl14-/- radial glia cells precociously express neuronal proteins. Further analysis uncovers previously unappreciated transcriptional pre-patterning in cortical neural stem cells. Comparison of m6A-mRNA landscapes between mouse and human cortical neural progenitors identifies human-specific tagging of transcripts related to epigenetic regulation and brain disorder risk genes. Our study reveals an epitranscriptomic mechanism in heightened transcriptional coordination during mammalian cortical neurogenesis.
2017-09-28 | GSE99017 | GEO
Project description:Postnatal brain neurogenesis in mammals is believed to be restricted to rare germinative remnants of the neuroepithelium. In this study, we discovered that, in the postnatal brain, a subset of embryonically derived progenitors is present in meningeal substructures. These cells migrate from the meningeal substructures to the retrosplenial and visual motor cortex and differentiate into (electrically) functional integrated neurons. Lineage tracing analysis revealed that this subset of neural progenitors originate largely from PDGFR+ cells. PDGFR-derived cells differentiate mostly into Satb2+ neurons in cortical layers I-IV. Thus, a reservoir of embryonically derived progenitors in the meninges contributes to postnatal cerebral cortical neurogenesis.
2016-11-23 | E-MTAB-4951 | biostudies-arrayexpress
Project description:The cerebral cortex contains layers of neurons sequentially generated by distinct lineage-related progenitors. At the onset of corticogenesis, the first-born progenitors are apical progenitors (APs) whose asymmetric division give birth directly to neurons. Later, they switch to indirect neurogenesis by generating intermediate progenitors (IPs), which give rise to projection neurons of all cortical layers. While a direct lineage relationship between APs and IPs has been established, the molecular mechanism that controls their transition remains elusive. Our data suggest that interfering with codon translation speed triggers endoplasmic reticulum stress and the unfolded protein response (UPR), further impairing the generation of IPs and leading to microcephaly. Moreover, we demonstrate that a progressive downregulation of UPR in cortical progenitors acts as physiological signal to amplify IPs and promotes indirect neurogenesis. Thus, our findings reveal a hitherto unrecognized contribution of UPR to cell fate acquisition during mammalian brain development. Ribosome profiling and RNA-Seq of forebrains from E14.5 mouse embryos from wild type animals and mutants carrying a conditional knockout of ELP3 in cortical progenitors
2015-12-11 | E-GEOD-74683 | biostudies-arrayexpress
Project description:All animals have specialized brain structures with a neuronal composition optimized for their survival and adaptation. The mammals share the laminar structure of the cerebral cortex, where a certain repertoire of excitatory neuron subtypes is arranged in specific tangential layers. However, the quantitative balance of subtypes is highly specialized in each species due to unknown developmental mechanisms. It is of particular interest to understand how the relatively conserved process of mammalian corticogenesis is modified in each species to achieve an optimized neuronal composition. Here, we show that fine-tuning the temporal progression of neurogenesis is the critical mechanism of the species-specific neuronal repertoire through our comparative study of mouse and rat cortical excitatory neurogenesis. Clonal tracing of individual progenitors revealed that rats produce more deep layer (DL) subtypes than mice, but both species produce essentially the same number of upper layer (UL) neurons. Such subtype-specific dosage optimization is mediated by the selective expansion of the early neurogenetic window for DL production in rats, as revealed by our neuronal birthdating and single cell transcriptomics. We found that the temporal neurogenetic status of the progenitors is encoded, at least in part, by Ccnd1 expression, as evidenced by the precocious UL production upon Ccnd1 knockdown in the rat mid-neurogenetic phase, when significant expression is maintained at levels comparable to the earlier phase in mice. Collectively, these results suggest that the closely related rodents, mouse and rat, construct their cortical structure with specific neuronal composition through the pinpointed specialization in developmental progression while maintaining the basic framework of the inside-out sequence of cortical excitatory neurogenesis. This study used mice and rats, the most common laboratory mammals with a close evolutionary relationship, to reveal the detailed molecular and cellular mechanisms behind the fine-tuning of cell composition in the cerebral cortex. Such a detailed comparison dissected the specialized and unchanged processes of corticogenesis during the evolutionary divergence of the two species. This further provides insights into the evolvability and developmental constraints of mammalian corticogenesis.
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Project description:N6-methyl-adenosine (m6A) is the most abundant modification on messenger RNAs and is linked to human diseases, but its functions in mammalian development are poorly understood. Here we reveal the evolutionary conservation and function of m6A by mapping the m6A methylome in mouse and human embryonic stem cells. Thousands of messenger and long noncoding RNAs show conserved m6A modification, including transcripts encoding core pluripotency transcription factors. m6A is enriched over 3M-bM-^@M-^Y untranslated regions at defined sequence motifs, and marks unstable transcripts, including transcripts turned over upon differentiation. Genetic inactivation or depletion of mouse and human Mettl3, one of the m6A methylases, led to m6A erasure on select target genes, prolonged Nanog expression upon differentiation, and impaired ESCM-bM-^@M-^Ys exit from self-renewal towards differentiation into several lineages in vitro and in vivo. Thus, m6A is a mark of transcriptome flexibility required for stem cells to differentiate to specific lineages. Examing m6A modification differences in two different cell types
2014-10-20 | E-GEOD-52600 | biostudies-arrayexpress
Project description:The development of the mammalian neocortex is precisely regulated by temporal gene expression, yet the temporal regulatory mechanisms of cortical neurogenesis, particularly how radial glial cells (RGCs) sequentially generate deep to superficial neurons, remain unclear. Here, the hnRNP family member Syncrip (hnRNP Q) is identified as a key modulator of superficial neuronal differentiation in neocortical neurogenesis. Syncrip knockout in RGCs disrupts differentiation and abnormal neuronal localization, ultimately resulting in superficial cortical layer defects as well as learning and memory impairments in mice. Single‐cell RNA sequencing analysis demonstrated that the knockout of Syncrip disrupts the late‐stage neurogenesis, stalling transcriptional progression in RGCs. Mechanistically, Syncrip maintains the transcription of temporal process‐related transcription factors by recruiting stabilization complexes through phase separation, crucially regulating the Notch signaling pathway that determines the fate of RGCs. Furthermore, pathogenic human mutations in Syncrip weaken its phase‐separation capability, failing to form stable complexes normally. Thus, Syncrip acts as a mediator of posttranscriptional regulatory mechanisms, governing the fate progression of RGCs and the advancement of intrinsic temporal programs. This study establishes an intracellular mechanism for posttranscriptional regulation of progressive fate determination in cortical neurogenesis.
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Project description:During cortical development neurons are generated sequentially from basal progenitors (BPs) which specifically express the transcription factor Tbr2. We used fluorescent-activaed cell sorting (FACS) to isolate BPs from Tbr2GFP knockin reporter mice (Arnold SJ et al. Genesis, 2009) at early (embryonic day, E13) and late (embryonic day, E16) stages of cortical neurogenesis and determined mRNA expression profiles using mouse mRNA microarray (Illumina MouseWG-6 v2). Comparison of E13 and E16 mRNA expression profiles allowed us to identify regulatory gene networks for maintaining stage specific homeostasis of BPs throughout neurogenesis. FACS isolated BPs at E13 and E16 mouse brain cortex were used for microarray analyses. Six biological replicates (embryonic cortex from three different litters) for E13 and five biological replicates (embryonic cortex from three different litters) for E16 were analysed.
2014-05-01 | E-GEOD-45450 | biostudies-arrayexpress
Project description:Meningeal cells contribute to postnatal cortical neurogenesis.
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Project description:Apical progenitors remain multipotent throughout cortical neurogenesis
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Project description:Gene regulatory networks controlling temporal patterning, neurogenesis, and cell fate specification in the mammalian retina.
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