A Critical Period in Cortical Interneuron Neurogenesis in Down Syndrome Revealed by Human Neural Progenitor Cells

Bhattacharyya, Anita; McMillan, Erin; Chen, Serene I.; Wallace, Kyle; Svendsen, Clive N.

doi:10.1159/000236899

Cited by 69 publications

(56 citation statements)

References 145 publications

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“…Overexpression of HSA21 located Olig1 and Olig2 have been shown to increase GABAergic interneuron neurogenesis in Ts65Dn mice, and the dysregulation of excitatoryinhibitory imbalance could be rescued by knocking down the extra copy of these two genes (Chakrabarti et al, 2010). This phenotype contrasts with our observations and those from other groups, who have observed a reduction of interneurons in DS HNPs at the expense of increasing oligodendrocytes (Bhattacharyya et al, 2009). We see a shift from neuronal to gliocentric progenitors with overexpression of S100B (Esposito et al, 2008a) and APP (unpublished observations), which would potentially further compromise the interneuron population.…”

Section: Imbalance Of Excitatory-inhibitory Neurotransmissioncontrasting

confidence: 99%

“…For example, the REST/NRSF transcription factor was previously reported to be selectively repressed in the DS HNPs (Bahn et al, 2002). These changes were not seen in our studies or those of others (Bhattacharyya et al, 2009;Esposito et al, 2008a). However, this discrepancy could be due to the fact that the gestational ages of the euploid and DS fetal tissues used in these differential expression studies were not the same.…”

Section: Temporal-spatial Mapping-based Clusterscontrasting

confidence: 77%

“…A shift in the DS progenitor pool may contribute to the neuronal reduction and increase in glial cells within the mature trisomy 21 brain. Some studies have suggested impairments in interneuron neurogenesis within the DS HNP pool, possibly due to over-expression of the transcription factor COUP-TF1/NR2F1 (Bhattacharyya et al, 2009). Increased levels of COUP-TF1/NR2F1 cause increases in the generation of earlier born neurons and depletion of later born interneurons.…”

Section: Gliosis and Inflammatory Changesmentioning

confidence: 99%

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Combinatorial Gene Effects on the Neural Progenitor Pool in Down Syndrome

Lu¹,

Sheen²

2011

Genetics and Etiology of Down Syndrome

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Section: Imbalance Of Excitatory-inhibitory Neurotransmissioncontrasting

confidence: 99%

Section: Temporal-spatial Mapping-based Clusterscontrasting

confidence: 77%

Section: Gliosis and Inflammatory Changesmentioning

confidence: 99%

See 1 more Smart Citation

Combinatorial Gene Effects on the Neural Progenitor Pool in Down Syndrome

Lu¹,

Sheen²

2011

Genetics and Etiology of Down Syndrome

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“…The reported reductions in cortical neurons in DS brains may affect primarily late-born neurons that are not being evaluated in our study (24,30,34,35).…”

Section: Resultsmentioning

confidence: 83%

Deficits in human trisomy 21 iPSCs and neurons

Weick

Held

Bonadurer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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179

214

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Down syndrome (trisomy 21) is the most common genetic cause of intellectual disability, but the precise molecular mechanisms underlying impaired cognition remain unclear. Elucidation of these mechanisms has been hindered by the lack of a model system that contains full trisomy of chromosome 21 (Ts21) in a human genome that enables normal gene regulation. To overcome this limitation, we created Ts21-induced pluripotent stem cells (iPSCs) from two sets of Ts21 human fibroblasts. One of the fibroblast lines had low level mosaicism for Ts21 and yielded Ts21 iPSCs and an isogenic control that is disomic for human chromosome 21 (HSA21). Differentiation of all Ts21 iPSCs yielded similar numbers of neurons expressing markers characteristic of dorsal forebrain neurons that were functionally similar to controls. Expression profiling of Ts21 iPSCs and their neuronal derivatives revealed changes in HSA21 genes consistent with the presence of 50% more genetic material as well as changes in non-HSA21 genes that suggested compensatory responses to oxidative stress. Ts21 neurons displayed reduced synaptic activity, affecting excitatory and inhibitory synapses equally. Thus, Ts21 iPSCs and neurons display unique developmental defects that are consistent with cognitive deficits in individuals with Down syndrome and may enable discovery of the underlying causes of and treatments for this disorder.cerebral cortex | developmental disorders D own syndrome (DS) is the most frequent single cause of human birth defects and intellectual disability (ID) (1). DS is caused by trisomy of chromosome 21 (Ts21) (2), resulting in the triplication of over 400 genes (3-5), which makes elucidation of the precise mechanisms underlying ID in DS a significant challenge. Confounding this difficulty is the relative inaccessibility of human tissue and incomplete human Ts21 in the context of mouse models. Despite these shortcomings, studies using mouse models containing trisomy of parts of syntenic chromosome 21 (HSA21) have put forth several critical hypotheses on the cellular and molecular mechanisms underlying DS features. It is essential, however, to test these hypotheses in human cells with full triplication of HSA21 in a context that allows for normal gene regulation. Here, we used Ts21-induced pluripotent stem cells (iPSCs) to test hypotheses of the underlying causes of ID in DS, with specific regard to neuropathophysiology. ResultsIsogenic Human Ts21 iPSCs. Fibroblasts from two individuals diagnosed with DS were reprogrammed to iPSCs. FISH for HSA21 in one fibroblast line showed mosaicism, where ∼90% of cells carried Ts21, whereas ∼10% were euploid (Fig. 1A). Reprogramming of the mosaic fibroblasts by retrovirus (6) resulted in three viable iPSC clones, two clones that carried Ts21 and one euploid (Fig. 1B). Mosaicism in DS individuals is rare, occurring in ∼1-3% of DS cases (7), but it can also emerge in vitro (8), potentially because of nondisjunction events during cell division.

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“…Changes in expression of various HSA21 genes can also regulate subpopulations of progenitors. For example, microarray profiling of DS human neuroprogenitors implicated a defect in interneuron neurogenesis through increased expression of glial progenitor genes such as OLIG1, OLIG2, OMG and COUP-TF1/NR2F1 and downregulation of the interneuron related genes DLX1, DLX2 and DLX5 [32].…”

Section: Genetics Mechanisms Underlying Neurogenesis In Dsmentioning

confidence: 99%