Neurogenesis and neuronal differentiation in the postnatal frontal cortex in Down syndrome

Utagawa, Emma; Moreno, David G; Schafernak, Kristian T.; Arva, Nicoleta C.; Malek‐Ahmadi, Michael; Mufson, Elliott J.; Perez, Sylvia E.

doi:10.1186/s40478-022-01385-w

Cited by 14 publications

(11 citation statements)

References 99 publications

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“…Downregulation of these genes is aligned with the notion that neurogenesis impairment is one of the preserved neuropathology seen in various DS models and causes cognitive impairment (Hwang & Zukin, 2018;Lott & Dierssen, 2010). Previous studies supported that the altered cell cycle can cause reduced cell proliferation which starts from the early embryonic to the postnatal development in various DS mouse models and human induced pluripotent stem cells (Contestabile et al, 2007;Ishihara, 2021;Stagni et al, 2018;Tang et al, 2021;Utagawa et al, 2022). Therefore, this GO analysis revealed that these cell cycle genes were targeted by REST and their downregulation in DS may be attributed to the REST dysregulation.…”

Section: Discussionmentioning

confidence: 60%

Spatiotemporal expression of Rest in the brain of Ts1Cje mouse model of Down syndrome

Lim

Lam

Crystal

et al. 2023

Preprint

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Introduction: Down syndrome (DS) is a common genetic disorder caused by full or partial trisomy of human chromosome 21. DS individuals usually have poor neurological development with neuropsychiatric manifestations. Repressor element-1 silencing transcription factor (REST) is the key regulator for epigenetic neuronal gene expression. REST nuclear translocation is crucial to exert repression on target genes transcriptionally. A comprehensive spatiotemporal profiling of Rest expression was performed on the Ts1Cje mouse brain to reveal its association with DS neuropathology development. Methods: Over-representation analysis of Ts1Cje differentially expressed genes (DEGs) with mouse REST targets was performed. The cerebral cortex, hippocampus and cerebellum of Ts1Cje and wildtype (WT) mice were procured at postnatal - P1, P15, P30, and P84 and embryonic - E14 and P1.5 development timepoints[User1] . RNAs from the brain tissues and cultured neurospheres were analysed with qPCR to determine the spatiotemporal profile of Rest expression. Western blot and immunohistochemistry (IHC) staining were performed to determine the level of REST expression and nuclear localisation. Results: Over-representation analysis showed the Ts1Cje DEGs are significantly overlapped with mouse REST target genes. QPCR and Western blot analysis revealed a significant downregulation of Rest in neurospheres and protein expression in Ts1Cje compared to WT. Furthermore, IHC staining showed a consistent perinuclear marginalisation of REST, indicating impaired nuclear translocation in the Ts1Cje brain. Conclusion:DEGs in the Ts1Cje tissues are potentially caused by the loss of REST functions. Dysregulated Rest expression at the early neurodevelopmental stage may cause premature neurodifferentiation, neural stem cell pool depletion, and disrupt early cell fate determination. The loss of nuclear REST function may cause neuroprotection and stress resilience deficits.

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Section: Discussionmentioning

confidence: 60%

Spatiotemporal expression of Rest in the brain of Ts1Cje mouse model of Down syndrome

Lim

Lam

Crystal

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Clinically, individuals with DS have an overall reduced brain volume. Hypocellularity has been associated with impaired neurogenesis and lower proliferative rate potency that can be observed as early as 24 weeks during gestation in the DS brain (Stagni et al, 2018 ; Utagawa et al, 2022 ). This phenomenon was not only observed in neurons but also in other cell types in vitro .…”

Section: Discussionmentioning

confidence: 99%

Alzheimer’s disease like neuropathology in Down syndrome cortical organoids

Zhao

Haddad

2022

Front. Cell. Neurosci.

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Introduction: Down syndrome (DS) is a genetic disorder with an extra copy of chromosome 21 and DS remains one of the most common causes of intellectual disabilities in humans. All DS patients have Alzheimer’s disease (AD)-like neuropathological changes including accumulation of plaques and tangles by their 40s, much earlier than the onset of such neuropathological changes in AD patients. Due to the lack of human samples and appropriate techniques, our understanding of DS neuropathology during brain development or before the clinical onset of the disease remains largely unexplored at the cellular and molecular levels.Methods: We used induced pluripotent stem cell (iPSC) and iPSC-derived 3D cortical organoids to model Alzheimer’s disease in Down syndrome and explore the earliest cellular and molecular changes during DS fetal brain development.Results: We report that DS iPSCs have a decreased growth rate than control iPSCs due to a decreased cell proliferation. DS iPSC-derived cortical organoids have a much higher immunoreactivity of amyloid beta (Aß) antibodies and a significantly higher amount of amyloid plaques than control organoids. Although Elisa results did not detect a difference of Aß40 and Aß42 level between the two groups, the ratio of Aß42/Aß40 in the detergent-insoluble fraction of DS organoids was significantly higher than control organoids. Furthermore, an increased Tau phosphorylation (pTau S396) in DS organoids was confirmed by immunostaining and Western blot. Elisa data demonstrated that the ratio of insoluble Tau/total Tau in DS organoids was significantly higher than control organoids.Conclusion: DS iPSC-derived cortical organoids mimic AD-like pathophysiologyical phenotype in vitro, including abnormal Aß and insoluble Tau accumulation. The molecular neuropathologic signature of AD is present in DS much earlier than predicted, even in early fetal brain development, illustrating the notion that brain organoids maybe a good model to study early neurodegenerative conditions.

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“…Ts65Dn mice and littermate CTLs were selected from three separate litters. The cerebral cortex, the outermost portion of the brain, was chosen as the region of interest for this study due to its involvement in cognition and higher-order processing 27 , and its known structural and function deficits in DS individuals, including reductions in cortical volume and surface area, as well as decreased cell counts, abnormal synapto-dendritic processes, and disorganized cortical lamination 28,29 . Through multi-omic single-nucleus sequencing, we analyzed the transcriptomes and epigenomes from each dataset using the well-established Seurat 30 and Signac 31 pipelines, respectively.…”

Section: Characterization Of Cell Types In the Adult Ts65dn Cortex Us...mentioning

confidence: 99%

Single-nucleus profiling identifies accelerated oligodendrocyte precursor cell senescence in a mouse model of Down Syndrome

Rusu

Kukreja

et al. 2023

Preprint

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Down Syndrome (DS), the most common genetic cause of intellectual disability, is associated with lifelong cognitive disability. However, the mechanisms by which triplication of human chromosome 21 genes drive neuroinflammation and cognitive dysfunction are poorly understood. Here, using the Ts65Dn mouse model of DS, we performed an integrated single-nucleus RNA- and ATAC-seq analysis of the cortex. We identify cell type-specific transcriptional and chromatin-associated changes in the Ts65Dn cortex, including regulators of neuroinflammation, transcription and translation, myelination, and mitochondrial function. We discover enrichment of a senescence-associated transcriptional signature in Ts65Dn oligodendrocyte precursor cells (OPCs) and epigenetic changes consistent with a loss of heterochromatin. We find that senescence is restricted to a subset of cortical OPCs concentrated in deep cortical layers. Treatment of Ts65Dn mice with a senescence-reducing flavonoid rescues cortical OPC proliferation, restores microglial homeostasis, and improves contextual fear memory. Together, these findings suggest that cortical OPC senescence may be an important driver of neuropathology in DS.

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Neurogenesis and neuronal differentiation in the postnatal frontal cortex in Down syndrome

Cited by 14 publications

References 99 publications

Spatiotemporal expression of Rest in the brain of Ts1Cje mouse model of Down syndrome

Spatiotemporal expression of Rest in the brain of Ts1Cje mouse model of Down syndrome

Alzheimer’s disease like neuropathology in Down syndrome cortical organoids

Single-nucleus profiling identifies accelerated oligodendrocyte precursor cell senescence in a mouse model of Down Syndrome

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