Chromosome 21 KIR channels in brain development

Potential Role of JAK-STAT Signaling Pathway in the Neurogenic-to-Gliogenic Shift in Down Syndrome Brain

Neural Plasticity ◽

10.1155/2016/7434191 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 16

Author(s):

Han-Chung Lee ◽

Kai-Leng Tan ◽

Pike-See Cheah ◽

King-Hwa Ling

Keyword(s):

Down Syndrome ◽

Brain Development ◽

Cell Fate ◽

Mouse Models ◽

Neuronal Cell ◽

Janus Kinase ◽

Chromosome 21 ◽

Severe Intellectual Disability ◽

Stat Signaling

Trisomy of human chromosome 21 in Down syndrome (DS) leads to several phenotypes, such as mild-to-severe intellectual disability, hypotonia, and craniofacial dysmorphisms. These are fundamental hallmarks of the disorder that affect the quality of life of most individuals with DS. Proper brain development involves meticulous regulation of various signaling pathways, and dysregulation may result in abnormal neurodevelopment. DS brain is characterized by an increased number of astrocytes with reduced number of neurons. In mouse models for DS, the pool of neural progenitor cells commits to glia rather than neuronal cell fate in the DS brain. However, the mechanism(s) and consequences of this slight neurogenic-to-gliogenic shift in DS brain are still poorly understood. To date, Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling has been proposed to be crucial in various developmental pathways, especially in promoting astrogliogenesis. Since both human and mouse models of DS brain exhibit less neurons and a higher percentage of cells with astrocytic phenotypes, understanding the role of JAK-STAT signaling in DS brain development will provide novel insight into its role in the pathogenesis of DS brain and may serve as a potential target for the development of effective therapy to improve DS cognition.

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Type I Interferon Signaling Drives Microglial Dysfunction and Senescence in Human iPSC Models of Down Syndrome and Alzheimers Disease

10.1101/2021.12.22.473858 ◽

2021 ◽

Author(s):

Mengmeng Jin ◽

Ranji Xu ◽

Mahabub Maraj Alam ◽

Ziyuan Ma ◽

Sining Zhu ◽

...

Keyword(s):

Down Syndrome ◽

Brain Development ◽

Type I Interferon ◽

Chromosome 21 ◽

Type I ◽

Chimeric Mouse ◽

Interferon Signaling ◽

Alzheimers Disease ◽

Human Microglia ◽

The Impact

Microglia are critical for brain development and play a central role in Alzheimers disease (AD) etiology. Down syndrome (DS), also known as trisomy 21, is the most common genetic origin of intellectual disability and the most common risk factor for AD. Surprisingly, little information is available on the impact of trisomy of human chromosome 21 (Hsa21) on microglia in DS brain development and AD in DS (DSAD). Using our new induced pluripotent stem cell (iPSC)-based human microglia-containing cerebral organoid and chimeric mouse brain models, here we report that DS microglia exhibit enhanced synaptic pruning function during brain development. Consequently, electrophysiological recordings demonstrate that DS microglial mouse chimeras show impaired synaptic neurotransmission, as compared to control microglial chimeras. Upon being exposed to human brain tissue-derived soluble pathological tau, DS microglia display dystrophic phenotypes in chimeric mouse brains, recapitulating microglial responses seen in human AD and DSAD brain tissues. Further flow cytometry, single-cell RNA-sequencing, and immunohistological analyses of chimeric mouse brains demonstrate that DS microglia undergo cellular senescence and exhibit elevated type I interferon signaling after being challenged by pathological tau. Mechanistically, we find that shRNA-mediated knockdown of Hsa21encoded type I interferon receptor genes, IFNARs, rescues the defective DS microglial phenotypes both during brain development and in response to pathological tau. Our findings provide first in vivo evidence supporting a paradigm shifting theory that human microglia respond to pathological tau by exhibiting accelerated senescence and dystrophic phenotypes. Our results further suggest that targeting IFNARs may improve microglial functions during DS brain development and prevent human microglial senescence in DS individuals with AD.

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Human iPSC-derived Down syndrome astrocytes display genome-wide perturbations in gene expression, an altered adhesion profile, and increased cellular dynamics

Human Molecular Genetics ◽

10.1093/hmg/ddaa003 ◽

2020 ◽

Vol 29 (5) ◽

pp. 785-802 ◽

Cited By ~ 5

Author(s):

Blandine Ponroy Bally ◽

W Todd Farmer ◽

Emma V Jones ◽

Selin Jessa ◽

J Benjamin Kacerovsky ◽

...

Keyword(s):

Extracellular Matrix ◽

Down Syndrome ◽

Cell Adhesion ◽

Brain Development ◽

Trisomy 21 ◽

Chromatin Accessibility ◽

Chromosome 21 ◽

Genome Wide ◽

And Function ◽

The Impact

Abstract Down syndrome (DS), caused by the triplication of human chromosome 21, leads to significant alterations in brain development and is a major genetic cause of intellectual disability. While much is known about changes to neurons in DS, the effects of trisomy 21 on non-neuronal cells such as astrocytes are poorly understood. Astrocytes are critical for brain development and function, and their alteration may contribute to DS pathophysiology. To better understand the impact of trisomy 21 on astrocytes, we performed RNA-sequencing on astrocytes from newly produced DS human induced pluripotent stem cells (hiPSCs). While chromosome 21 genes were upregulated in DS astrocytes, we found consistent up- and down-regulation of genes across the genome with a strong dysregulation of neurodevelopmental, cell adhesion and extracellular matrix molecules. ATAC (assay for transposase-accessible chromatin)-seq also revealed a global alteration in chromatin state in DS astrocytes, showing modified chromatin accessibility at promoters of cell adhesion and extracellular matrix genes. Along with these transcriptomic and epigenomic changes, DS astrocytes displayed perturbations in cell size and cell spreading as well as modifications to cell-cell and cell-substrate recognition/adhesion, and increases in cellular motility and dynamics. Thus, triplication of chromosome 21 is associated with genome-wide transcriptional, epigenomic and functional alterations in astrocytes that may contribute to altered brain development and function in DS.

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Astrocytes in Down Syndrome Across the Lifespan

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.702685 ◽

2021 ◽

Vol 15 ◽

Author(s):

Blandine Ponroy Bally ◽

Keith K. Murai

Keyword(s):

Down Syndrome ◽

Brain Development ◽

Chromosome 21 ◽

Early Brain Development ◽

The Central Nervous System ◽

Circuit Development ◽

And Function ◽

The Impact ◽

The Brain

Down Syndrome (DS) is the most common genetic cause of intellectual disability in which delays and impairments in brain development and function lead to neurological and cognitive phenotypes. Traditionally, a neurocentric approach, focusing on neurons and their connectivity, has been applied to understanding the mechanisms involved in DS brain pathophysiology with an emphasis on how triplication of chromosome 21 leads to alterations in neuronal survival and homeostasis, synaptogenesis, brain circuit development, and neurodegeneration. However, recent studies have drawn attention to the role of non-neuronal cells, especially astrocytes, in DS. Astrocytes comprise a large proportion of cells in the central nervous system (CNS) and are critical for brain development, homeostasis, and function. As triplication of chromosome 21 occurs in all cells in DS (with the exception of mosaic DS), a deeper understanding of the impact of trisomy 21 on astrocytes in DS pathophysiology is warranted and will likely be necessary for determining how specific brain alterations and neurological phenotypes emerge and progress in DS. Here, we review the current understanding of the role of astrocytes in DS, and discuss how specific perturbations in this cell type can impact the brain across the lifespan from early brain development to adult stages. Finally, we highlight how targeting, modifying, and/or correcting specific molecular pathways and properties of astrocytes in DS may provide an effective therapeutic direction given the important role of astrocytes in regulating brain development and function.

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