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Expression profiling analysis of mouse E10.5 Magoh mutant brain cortices

ABSTRACT: Human brain structure and size requires regulated division of neural stem cells (NSCs). NSCs undergo precise divisions to self-renew and to produce intermediate neural progenitors (INPs) and neurons. The factors that regulate NSC divisions remain poorly understood, as do mechanistic explanations of how aberrant NSC division causes reduced brain size, as seen in microcephaly. Here we demonstrate that Magoh, a component of the core exon junction complex (EJC) that binds spliced RNA, controls cerebral cortical size by regulating NSC division. Magoh haploinsufficiency causes microcephaly due to INP depletion, neuronal apoptosis, and improper mitotic spindle orientation. Defective mitosis underlies these phenotypes as depletion of EJC components disrupts mitotic spindle integrity, chromosome number and genomic stability. We show that an essential function of Magoh is to regulate expression of the human microcephaly protein, LIS1, and that Lis1 addition rescues neurogenesis defects caused by Magoh knockdown, thus providing a genetic explanation for the microcephaly. This study uncovers new requirements for the EJC in brain development, NSC maintenance, mitosis and chromosome stability, thus implicating this complex in the pathogenesis of microcephaly. Mouse embryonic cortices were used for expression analysis 5 biological replicates each of control (C57BL/6) and Magoh mutant brains were analyzed

ORGANISM(S): Mus musculus

SUBMITTER: Tarran Pierfelice

PROVIDER: E-GEOD-19168 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression profiling analysis of mouse E10.5 Magoh mutant brain cortices

Project description:Human brain structure and size requires regulated division of neural stem cells (NSCs). NSCs undergo precise divisions to self-renew and to produce intermediate neural progenitors (INPs) and neurons. The factors that regulate NSC divisions remain poorly understood, as do mechanistic explanations of how aberrant NSC division causes reduced brain size, as seen in microcephaly. Here we demonstrate that Magoh, a component of the core exon junction complex (EJC) that binds spliced RNA, controls cerebral cortical size by regulating NSC division. Magoh haploinsufficiency causes microcephaly due to INP depletion, neuronal apoptosis, and improper mitotic spindle orientation. Defective mitosis underlies these phenotypes as depletion of EJC components disrupts mitotic spindle integrity, chromosome number and genomic stability. We show that an essential function of Magoh is to regulate expression of the human microcephaly protein, LIS1, and that Lis1 addition rescues neurogenesis defects caused by Magoh knockdown, thus providing a genetic explanation for the microcephaly. This study uncovers new requirements for the EJC in brain development, NSC maintenance, mitosis and chromosome stability, thus implicating this complex in the pathogenesis of microcephaly. Mouse embryonic cortices were used for expression analysis

2010-04-04 | GSE19168 | GEO

A mechanism for the segregation of age in mammalian neural stem cells

Project description:Across life neural stem cells (NSCs) generate new neurons in the mammalian brain through asymmetric neurogenic and self-renewing cell divisions. However, the cellular mechanisms underlying NSC asymmetry remain unknown. Using fluorescence loss in photobleaching (FLIP) we here show that NSCs in vitro and within the developing forebrain generate a lateral diffusion barrier during cell division resulting in asymmetric segregation of cellular components. The strength of the diffusion barrier is dynamically regulated with age and depends on the proper function of lamin-associated nuclear envelope constituents. Strikingly, age-associated or experimental impairment of the diffusion barrier disrupts asymmetric segregation of damaged proteins, a product of aging. Thus, the data presented here identify a mechanism how age is asymmetrically distributed during somatic stem cell division. For microarray analysis we analysed gene expression in cells derived from the hippocampi of 6 week old (young) or 9 month old (old) male C57BL/6JRj mice. 6 samples were analyzed YoungNSC, 3 replicates OldNSC, 3 replicates

2015-09-22 | E-GEOD-61367 | biostudies-arrayexpress

A mechanism for the segregation of age in mammalian neural stem cells

2015-09-22 | GSE61367 | GEO

Rack1 is Essential for Corticogenesis by Preventing P21-Dependent Senescence in Neural Stem Cells

Project description:Normal neurodevelopment relies on intricate signaling pathways that balance neural stem cell (NSC) self-renewal, maturation and survival. Disruptions lead to neurodevelopmental disorders including microcephaly. Here, we implicate the inhibition of NSC senescence as a mechanism underlying neurogenesis and corticogenesis. We report that the receptor for activated C kinase (Rack1), a family member of WD40-repeat (WDR) proteins, is highly enriched in NSCs. Deletion of Rack1 in developing cortical progenitors leads to a microcephaly phenotype. Strikingly, the absence of Rack1 decreases neurogenesis and promotes a cellular senescence phenotype in NSCs. Mechanistically, the senescence-related p21 signaling pathway is dramatically activated in Rack1-null NSCs, and removal of p21 significantly rescues the Rack1-knockout phenotype in vivo. Finally, Rack1 directly interacts with Smad3 to suppress the activation of TGF-β/Smad signaling pathway, which plays a critical role in p21-mediated senescence. Our data implicate Rack1-driven inhibition of p21-induced NSC senescence as a critical mechanism behind normal cortical development.

2021-08-09 | PXD027798 |

Enhanced cortical neural stem cell identity through SMAD/WNT inhibition in human cerebral organoids facilitates emergence of outer radial glial cells

Project description:Cerebral organoids exhibit broad regional heterogeneity accompanied by limited cortical cellular diversity despite the tremendous upsurge in derivation methods, suggesting inadequate patterning of early neural stem cells (NSCs). Here we show that a short and early dual-SMAD/WNT inhibition course is necessary and sufficient for establishing robust and lasting cortical organoid NSC identity, efficiently suppressing of non-cortical NSC fates, while other widely used methods are inconsistent in their cortical NSC specification capacity. Accordingly, this method selectively enriches for outer radial glia (oRG) NSCs, which cytoarchitecturally demarcate well-defined outer sub-ventricular (oSVZ)-like regions propagating from superiorly radially organized, apical cortical rosette NSCs. Finally, this method culminates in the emergence of molecularly distinct deep and upper cortical layer neurons, and reliably uncovers cortex-specific microcephaly defects. Thus, a short SMAD/WNT inhibition is critical for establishing a rich cortical cell repertoire that enables mirroring fundamental molecular and cytoarchitectural features of cortical development and meaningful disease modeling.

| EGAS00001006063 | EGA

Declining Lamin B1 expression mediates age-dependent decreases of hippocampal stem cell activity

Project description:Neural stem cells (NSCs) generate neurons throughout life in the hippocampal dentate gyrus (DG). With advancing age levels of neurogenesis sharply drop, which has been associated with a decline in hippocampal memory function. However, cell-intrinsic mechanisms mediating age-related changes in NSC activity remain largely unknown. Here we show that the nuclear lamina protein Lamin B1 (LB1) is downregulated with age in mouse hippocampal NSCs. LB1 is cross-regulated with Sun-domain containing protein 1 (SUN1), previously implicated in Hutchinson-Gilford progeria syndrome (HGPS), a disease of premature aging. LB1 and SUN1 govern the strength of a diffusion barrier in the membrane of the endoplasmic reticulum (ER) that is associated with the segregation of aging factors during NSC divisions. Balancing the levels of LB1 and SUN1 in aged NSCs restores the ER-diffusion barrier. Virus-based restoration of LB1 expression in aged NSCs enhances stem cell activity in vitro and increases progenitor cell proliferation and neurogenesis in vivo. Thus, we here identify a novel mechanism associated with the age-related decline of neurogenesis in the mammalian hippocampus.

2020-12-24 | GSE163795 | GEO

Transient knockdown of LIS1 results in seizures, differential gene expression and a neuronal migration disorder in developing zebrafish

Project description:Mutation or deletion of LIS1 (Lissencephaly-1) underlies classical lissencephaly, a migration disorder resulting in brain malformation, epilepsy and mental retardation. Orthologues for LIS1 genes (lis1a and lis1b) are ubiquitously expressed in developing zebrafish larvae, but the functional consequences of Lis1 knockdown are unknown. Here we used lis1-specific morpholino oligonucleotides (MOs, targeting protein translation or mRNA splicing, respectively) to transiently knockdown Lis1 expression in zebrafish. Injection of lis1 MOs resulted in morphological changes including microcephaly. At four days post-fertilization, lis1 morphants exhibited spontaneous convulsive behavior and abnormal large-amplitude electrographic discharge resembling that seen in acute and genetic zebrafish models of epilepsy. Abnormal brain development and neuronal migration defects were observed when lis1 MO injections were made into fluorescent reporter lines demarcating interneuron distribution (Dlx5a/6a:GFP) and brain structure (GBT0133:mRFP). Microarray analysis for ~44,000 Danio rerio transcripts identified 215 up-regulated and 160 down-regulated genes. Quantitative PCR and whole-mount in situ hybridization were used to validate these results for twenty and seven genes, respectively. These findings in a simple vertebrate model reproducing neuroanatomical and epileptic hallmarks of the human condition represent a novel approach to the study of childhood seizure disorders associated with a single gene mutation 4 WT samples (sample= 10 pooled larvae) and 4 Lis1Morphants slight phenotype (sample= 10 pooled larvae) were collected at 4dpf (days post fertilization). The morphants were selected based on phenotype and seizure behavior. Both groups of fish derived from same pools of eggs

2013-06-15 | E-GEOD-47952 | biostudies-arrayexpress

Early Stem Cell Aging in the Mature Brain

Project description:Stem cell dysfunction drives many age-related disorders. Identifying mechanisms that initially compromise stem cell behavior represent early targets to enhance stem cell function later in life. Here, we pinpoint multiple factors that disrupt neural stem cell (NSC) behavior in the adult hippocampus. Clonal tracing showed that NSCs exhibit asynchronous depletion by identifying short-term (ST-NSC) and long-term NSCs (LT-NSCs). ST-NSC divide rapidly to generate neurons and deplete in the young brain. Meanwhile, multipotent LT-NSCs are maintained for months, but are pushed out of homeostasis by lengthening quiescence. Single cell transcriptome analysis of deep NSC quiescence revealed several hallmarks of molecular aging in the mature brain and identified tyrosine-protein kinase Abl1 as an NSC pro-aging factor. Treatment with the Abl-inhibitor Imatinib increased NSC proliferation without impairing NSC maintenance in the middle-aged brain. Our study indicates that hippocampal NSCs are particularly vulnerable to cellular aging, yet NSC function can be partially restored.

2021-03-03 | GSE168031 | GEO

Transient knockdown of LIS1 results in seizures, differential gene expression and a neuronal migration disorder in developing zebrafish

2013-06-15 | GSE47952 | GEO

NSC-derived exosomes enhance therapeutic effects of NSC transplantation on cerebral ischemia in mice

Project description:Transplantation of neural stem cells (NSCs) has been proved to promote functional rehabilitation of brain lesions including ischemic stroke. However, the therapeutic effects of NSC transplantation is limited by the low survival and differentiation rates of NSCs due to the harsh environment in the brain after ischemic stroke. Here, we employed NSCs derived from human induced pluripotent stem cells (iPSCs) together with exosomes extracted from NSCs to treat cerebral ischemia induced by middle cerebral artery occlusion/reperfusion (MCAO/R) in mice. The results showed that NSC-derived exosomes significantly reduced the inflammatory response, alleviated oxidative stress after NSC transplantation, and facilitated NSCs differentiation in vivo. The combination of NSCs with exosomes ameliorated the injury of brain tissue including cerebral infarct, neuronal death and glial scarring, and promoted the motor function recovery. To explore the underlying mechanisms, we analyzed the miRNA profiles of NSC-derived exosomes and the potential downstream genes. Our study provided the rationale for the clinical application of NSC-derived exosomes as a supportive adjuvant for NSC transplantation after stroke.

2023-04-26 | GSE217074 | GEO

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