TRNP1 regulates expansion and folding of the mammalian cerebral cortex by control of radial glial fate
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE40582 | GEO | 2013/04/26
SECONDARY ACCESSION(S): PRJNA174341
REPOSITORIES: GEO
Similar Datasets
Project description:Evolution of the mammalian brain encompassed a remarkable increase in size of cerebral cortex, including tangential and radial expansion, but the mechanisms underlying these key parameters are still largely unknown. Here, we identified the novel DNA associated protein TRNP1 as a regulator of cerebral cortical expansion in both these dimensions. Gain and loss of function experiments in the mouse cerebral cortex in vivo demonstrate that high Trnp1 levels promote neural stem cell self-renewal and tangential expansion, while lower levels promote radial expansion resulting in a potent increase in the generation of intermediate progenitors and outer radial glial cells resulting in folding of the otherwise smooth murine cerebral cortex. Remarkably, TRNP1 expression levels exhibit regional differences also in the cerebral cortex of human fetuses anticipating radial or tangential expansion respectively. Thus, the dynamic regulation of TRNP1 is critical to regulate tangential and radial expansion of the cerebral cortex in mammals. We performed gene expression microarray analysis on embryonic mouse cerebral cortex derived from Trnp1 knockdown and control animals.
2013-04-26 | E-GEOD-40582 | biostudies-arrayexpress
Project description:Since the discovery of radial glia as the source of neurons, their heterogeneity in regard to neurogenesis has been described by clonal and time-lapse analysis in vitro. However, the molecular determinants specifying neurogenic radial glia differently from radial glia that mostly self-renew remain ill-defined. Here, we isolated two radial glial subsets that co-exist at mid-neurogenesis in the developing cerebral cortex and their immediate progeny. While one subset generates neurons directly, the other is largely non-neurogenic but also gives rise to Tbr2-positive basal precursors, thereby contributing indirectly to neurogenesis. Isolation of ; these distinct radial glia subtypes allowed determining interesting differences in their transcriptome. These transcriptomes were also strikingly different from the transcriptome of radial glia isolated at the end of neurogenesis. This analysis therefore identifies, for the first time, the lineage origin of basal progenitors and the molecular differences of this lineage in comparison to directly neurogenic and gliogenic radial glia. Experiment Overall Design: Comparison of radial glial subtypes
2008-06-18 | E-GEOD-8034 | biostudies-arrayexpress
Project description:Since the discovery of radial glia as the source of neurons, their heterogeneity in regard to neurogenesis has been described by clonal and time-lapse analysis in vitro. However, the molecular determinants specifying neurogenic radial glia differently from radial glia that mostly self-renew remain ill-defined. Here, we isolated two radial glial subsets that co-exist at mid-neurogenesis in the developing cerebral cortex and their immediate progeny. While one subset generates neurons directly, the other is largely non-neurogenic but also gives rise to Tbr2-positive basal precursors, thereby contributing indirectly to neurogenesis. Isolation of these distinct radial glia subtypes allowed determining interesting differences in their transcriptome. These transcriptomes were also strikingly different from the transcriptome of radial glia isolated at the end of neurogenesis. This analysis therefore identifies, for the first time, the lineage origin of basal progenitors and the molecular differences of this lineage in comparison to directly neurogenic and gliogenic radial glia.
2008-05-29 | GSE8034 | GEO
Project description:PNPLA8, one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological conditions through the maintenance of membrane phospholipids. However, little is known about its role in brain development. Here, we report 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide spectrum of clinical features ranging from developmental and epileptic-dyskinetic encephalopathy (DEDE) to progressive movement disorders and no phenotype depending on the variants and their positions. Complete loss of PNPLA8 was associated with the severe end of the spectrum showing DEDE manifestations and congenital or progressive microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells (iPSCs), we found that loss of PNPLA8 reduces the abundance of basal radial glial cells (bRGCs) and upper-layer neurons. By spatial transcriptomic analysis targeting apical radial glial cells (aRGCs), we found the downregulation of bRGC-related gene sets in patient-derived cerebral organoids. Lipidomic analysis revealed a decrease in the amount of lysophosphatidic acid, lysophosphatidylethanolamine, and phosphatidic acid, indicative of the disturbed phospholipid metabolism in PNPLA8 knockout neural progenitor cells. Our data suggest that PNPLA8 has a critical role in the bRGC-mediated expansion of the developing human cortex by regulating the fate commitment of aRGCs.
2024-03-05 | GSE248252 | GEO
Project description:PNPLA8, one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological conditions through the maintenance of membrane phospholipids. However, little is known about its role in brain development. Here, we report 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide spectrum of clinical features ranging from developmental and epileptic-dyskinetic encephalopathy (DEDE) to progressive movement disorders and no phenotype depending on the variants and their positions. Complete loss of PNPLA8 was associated with the severe end of the spectrum showing DEDE manifestations and congenital or progressive microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells (iPSCs), we found that loss of PNPLA8 reduces the abundance of basal radial glial cells (bRGCs) and upper-layer neurons. By spatial transcriptomic analysis targeting apical radial glial cells (aRGCs), we found the downregulation of bRGC-related gene sets in patient-derived cerebral organoids. Lipidomic analysis revealed a decrease in the amount of lysophosphatidic acid, lysophosphatidylethanolamine, and phosphatidic acid, indicative of the disturbed phospholipid metabolism in PNPLA8 knockout neural progenitor cells. Our data suggest that PNPLA8 has a critical role in the bRGC-mediated expansion of the developing human cortex by regulating the fate commitment of aRGCs.ナカセンセイキニュウ
2023-05-03 | GSE229956 | GEO
Project description:During embryonic development, the cerebral cortex is equipped with excitatory projection and inhibitory interneurons that migrate in organized layers. Periventricular heterotopia (PH) is a rare and heterogeneous disorder in which a subpopulation of new-born projection neurons fails to initiate their radial migration to the cortex, ultimately resulting in bands or nodules of grey matter lining the lateral ventricles underneath a normal cortex. For many years, few genes had been identified that cause this disorder upon disruption, but recently it was shown that PH is genetically a very heterogeneous disease. Here, we study the neurodevelopmental role of endothelin converting enzyme 2 (ECE2), biallelic mutations in which have been identified in two patients with PH. Our results show that manipulation of ECE2 levels or activity in human cerebral organoids and in the developing mouse cortex leads to ectopic localization of neural progenitors and neurons. We uncover the role of ECE2 in neurogenesis and, mechanistically, we identify its involvement in generation and secretion of extracellular matrix and in protein phosphorylation. This strongly suggests ECE2 as a novel candidate gene for PH.
2020-03-09 | PXD015571 | Pride
Project description:Tangential sections of 30 µm thickness were taken across the secondary phloem and developing secondary xylem, sections were then pooled to represent the tissues from specific developmental stages. Phloem (P) comprises 3 sections, the cambium (C) - 2 sections, the radial expansion zone (E) - 4 sections, the first to third xylem development zones (X1-X3) - 3 sections each, and the forth to sixth xylem development zones (X4-X6) - 6 sections each.
2017-06-23 | PXD005715 | Pride
Project description:The human cerebral cortex depends for its normal development and size on a precisely controlled balance between self-renewal and differentiation of diverse neural progenitor cells. Specialized progenitors that are common in humans, but virtually absent in rodents, called â??outer radial gliaâ?? (ORG), have been suggested to be crucial to the evolutionary expansion of the human cortex. We combined cell type-specific sorting with transcriptome-wide RNA-sequencing to identify genes enriched in human ORG, including targets of the transcription factor Neurogenin, and previously uncharacterized, evolutionarily dynamic, long noncoding RNAs. Single-cell transcriptional profiling of human, ferret, and mouse progenitors showed that more human RGC co-express proneural Neurogenin targets than in ferret or mouse, suggesting greater self-renewal of neuronal lineage-committed progenitors in humans. Finally, we show that activating the Neurogenin pathway in ferret RGC promotes delamination and outward migration. Thus, we find that the abundance of human ORG is paralleled by increased transcriptional heterogeneity of cortical progenitors. Three biological replicates of human late mid-fetal cortex (18 to 19 weeks of gestation) were dissociated and immunolabeled. Apical and outer radial glial cells were purified by FACS and compared to an immunonegative population, predominantly neurons.
2015-02-24 | E-GEOD-66217 | biostudies-arrayexpress
Project description:The homeobox containing gene Arx is expressed during ventral telencephalon development and it is required for correct GABAergic interneuron tangential migration from the ganglionic eminences to the olfactory bulbs, cerebral cortex and striatum. Its human ortholog is associated with a variety of neurological clinical manifestations whose syntoms are compatible with a loss of cortical interneurons and altered basal ganglia related-activities in humans. Herein, we reported the identification by global expression profiling of a group of genes whose expression is consistently altered in Arx mutant ganglionic eminences. Following analysis revealed the striking ectopic expression in the ganglionic eminences of a number of genes normally not, or only marginally, expressed in the ventral telencephalon. Among them, we functionally analyzed Ebf3, whose ectopic expression in ventral telencephalon is preventingneuronal tangential migration. Further, we showed that Arx is sufficient to repress Ebf3 endogenous expression and that its silencing in Arx mutant tissue might marginally rescue tangential cell movements. Together, these data provide an initial analysis of the molecular pathways regulated by Arx and how their networking might regulate those specific cellular processes during telencephalon development strongly altered by loss of Arx. Three timed-pregnant Arx heterozygous dams crossed with C57Bl/6 males were sacrificed at E14.5, the embryos harvested and placed into cold PBS. After brain isolarion, meninges and olfactory bulbs were removed, and the ventral telencephalon separated from the overlying cerebral cortex. The same procedure was repeated for 5 wt and 5 Arx mutant embryos.
2010-03-09 | E-GEOD-12956 | biostudies-arrayexpress
Project description:<p>We sought to characterize cellular heterogeneity in the human cerebral cortex at a molecular level during cortical neurogenesis. We captured single cells and generated sequencing libraries using the C1TM Single-Cell Auto Prep System (Fluidigm), the SMARTer Ultra Low RNA Kit (Clontech), and the Nextera XT DNA Sample Preparation Kit (Illumina). We performed unbiased clustering of the single cells and further examined transcriptional variation among cell groups interpreted as radial glia. Within this population, the major sources of variation related to cell cycle progression and the stem cell niche from which radial glia were captured. We found that outer subventricular zone radial glia (oRG cells) preferentially express genes related to extracellular matrix formation, migration, and stemness, including <i>TNC</i>, <i>PTPRZ1</i>, <i>FAM107A</i>, <i>HOPX</i>, and <i>LIFR</i> and related this transcriptional state to the position, morphology, and cell behaviors previously used to classify the cell type. Our results suggest that oRG cells maintain the subventricular niche through local production of growth factors, potentiation of growth factor signals by extracellular matrix proteins, and activation of self-renewal pathways, thereby contributing to the developmental and evolutionary expansion of the human neocortex.</p> <p>For <b>study version 2</b>, we have updated this data set to include additional primary cells that we infer to represent microglia, endothelial cells, and immature astrocytes, as well as additional cells from the developing neural retina, and from iPS-cell derived cerebral organoids. The genes distinguishing these cell populations may reveal biological processes supporting the diverse functions of these cell types as well as vulnerabilities of specific cell types in human genetic diseases and in viral infections.</p> <p>For <b>study version 3</b>, we have updated the data set to include additional primary cells, including those published in Nowakowski, et al., Science 2017: "Spatiotemporal Gene Expression Trajectories Reveal Developmental Hierarchies of the Human Cortex" (<i>in press</i>)</p>
| phs000989 | dbGaP