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Biphasic Cell Cycle Defect Causes Impaired Neurogenesis in Down Syndrome

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE95553 | GEO | 2022/10/05

REPOSITORIES: GEO

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Biphasic cell cycle defect causes impaired neurogenesis in down syndrome.

Project description:Impaired neurogenesis in Down syndrome (DS) is characterized by reduced neurons, increased glial cells, and delayed cortical lamination. However, the underlying cause for impaired neurogenesis in DS is not clear. Using both human and mouse iPSCs, we demonstrate that DS impaired neurogenesis is due to biphasic cell cycle dysregulation during the generation of neural progenitors from iPSCs named the "neurogenic stage" of neurogenesis. Upon neural induction, DS cells showed reduced proliferation during the early phase followed by increased proliferation in the late phase of the neurogenic stage compared to control cells. While reduced proliferation in the early phase causes reduced neural progenitor pool, increased proliferation in the late phase leads to delayed post mitotic neuron generation in DS. RNAseq analysis of late-phase DS progenitor cells revealed upregulation of S phase-promoting regulators, Notch, Wnt, Interferon pathways, and REST, and downregulation of several genes of the BAF chromatin remodeling complex. NFIB and POU3F4, neurogenic genes activated by the interaction of PAX6 and the BAF complex, were downregulated in DS cells. ChIPseq analysis of late-phase neural progenitors revealed aberrant PAX6 binding with reduced promoter occupancy in DS cells. Together, these data indicate that impaired neurogenesis in DS is due to biphasic cell cycle dysregulation during the neurogenic stage of neurogenesis.

| S-EPMC9596798 | biostudies-literature

Biphasic Cell Cycle Defect Causes Impaired Neurogenesis in Down Syndrome [CPC RNA-Seq]

Project description:Using integrative approach involving human and mouse iPSCs, we have unravelded the cellular and molecular mechanisms of reduced neurogenesis in Down syndome

2022-10-05 | GSE95552 | GEO

Biphasic Cell Cycle Defect Causes Impaired Neurogenesis in Down Syndrome [Pluripotency, RNA-Seq]

Project description:Using integrative approach involving human and mouse iPSCs, we have unravelded the cellular and molecular mechanisms of reduced neurogenesis in Down syndome

2022-10-05 | GSE95551 | GEO

Biphasic Cell Cycle Defect Causes Impaired Neurogenesis in Down Syndrome [PAX6 ChIP-Seq]

Project description:Using integrative approach involving human and mouse iPSCs, we have unravelded the cellular and molecular mechanisms of reduced neurogenesis in Down syndome

2022-10-05 | GSE95550 | GEO

Biphasic Cell Cycle Defect Causes Impaired Neurogenesis in Down Syndrome

Project description:Biphasic Cell Cycle Defect Causes Impaired Neurogenesis in Down Syndrome

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Modelling and rescuing neurodevelopmental defect of Down syndrome using induced pluripotent stem cells from monozygotic twins discordant for trisomy 21

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-12-01 | E-GEOD-52251 | biostudies-arrayexpress

S100B and APP promote a gliocentric shift and impaired neurogenesis in Down syndrome neural progenitors.

Project description:Down syndrome (DS) is a developmental disorder associated with mental retardation (MR) and early onset Alzheimer's disease (AD). These CNS phenotypes are attributed to ongoing neuronal degeneration due to constitutive overexpression of chromosome 21 (HSA21) genes. We have previously shown that HSA21 associated S100B contributes to oxidative stress and apoptosis in DS human neural progenitors (HNPs). Here we show that DS HNPs isolated from fetal frontal cortex demonstrate not only disturbances in redox states within the mitochondria and increased levels of progenitor cell death but also transition to more gliocentric progenitor phenotypes with a consequent reduction in neuronogenesis. HSA21 associated S100B and amyloid precursor protein (APP) levels are simultaneously increased within DS HNPs, their secretions are synergistically enhanced in a paracrine fashion, and overexpressions of these proteins disrupt mitochondrial membrane potentials and redox states. HNPs show greater susceptibility to these proteins as compared to neurons, leading to cell death. Ongoing inflammation through APP and S100B overexpression further promotes a gliocentric HNPs phenotype. Thus, the loss in neuronal numbers seen in DS is not merely due to increased HNPs cell death and neurodegeneration, but also a fundamental gliocentric shift in the progenitor pool that impairs neuronal production.

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Down Syndrome

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-01-25 | GSE196447 | GEO

Environmental enrichment rescues postnatal neurogenesis defect in the male and female Ts65Dn mouse model of Down syndrome.

Project description:Down syndrome (DS), the most frequent genetic cause of intellectual disability and developmental delay, results from impaired neural stem cell proliferation and differentiation. Impaired neurogenesis in the neocortex, hippocampus and cerebellum is believed to be the underlying cause of learning and behavioral deficits in the Ts65Dn mouse model of DS. Aggressive sensorimotor and cognitive therapies have shown promise in mitigating the cognitive disabilities in DS but these behavioral therapies have not yet been investigated at the cellular level. Here, using the Ts65Dn mouse model of DS, we demonstrate that a combination of environmental enrichment and physical exercise starting in juvenile mice (postnatal day 18) markedly increases cell proliferation, neurogenesis and gliogenesis in the hippocampal dentate gyrus (DG) and the forebrain subventricular zone (SVZ) of both male and female mice. Enrichment and exercise increased the rate of Ts65Dn DG neurogenesis to be comparable to that of the nonenriched euploid group, while the effect on SVZ neurogenesis was reduced and seen only after prolonged exposure. These results clearly indicate that in a comprehensive stimulatory environment, the postnatal DS brain has the intrinsic capability of improving neurogenesis and gliogenesis to the levels of normal matched controls and that this cellular response underlies the cognitive improvement seen following behavioral therapies.

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Down syndrome study

Project description:This SuperSeries is composed of the SubSeries listed below.

2009-02-23 | GSE14105 | GEO