Modeling Williams syndrome with induced pluripotent stem cells

Chailangkarn, Thanathom; Muotri, Alysson R.

doi:10.1080/23262133.2017.1283187

Cited by 12 publications

(10 citation statements)

References 59 publications

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“…This is a GABA transporter, suggesting that inhibitory signaling could be altered in the hippocampus. This gene has also been shown to decreased in WS-derived cortical neurons (23). Also of note, the Iqgap2 gene was shown to be elevated in the CD animals compared to WT animals.…”

Section: Resultsmentioning

confidence: 95%

“…Among these genes is Slc23a1 , the GABA vesicle transporter, which is down regulated in CD animals. Interestingly this gene was also found to be down regulated in human iPSC derived neurons from individuals with WS (23). This points to aberrant inhibitory activity in the CD brain, which could lead to functional deficits.…”

Section: Discussionmentioning

confidence: 98%

“…To overcome this second barrier, researchers have turned to using patient induced pluripotent stem cells to study the effects of the WSCR deletion and duplication on different disease relevant cell types (23–27). While linking molecular changes to organismal behavior is not possible with cell lines, this approach is amenable to studying cellular and molecular phenotypes, such as changes to the transcriptome and cellular physiology.…”

Section: Introductionmentioning

confidence: 99%

“…While linking molecular changes to organismal behavior is not possible with cell lines, this approach is amenable to studying cellular and molecular phenotypes, such as changes to the transcriptome and cellular physiology. By studying differentiated neural precursor cells from an individual with a typical WS deletion and an individual with an atypical deletion that spares the copy number of the FZD9 gene, Chailangkarn et al (23) showed that FZD9 is responsible for some of the cellular phenotypes, such as increased apoptosis and morphological changes. Lalli et al (25) used a similar approach to show that knocking down the BAZ1B gene in differentiated neurons was sufficient to reproduce the transcriptional differences and deficits in differentiation that were observed in WS differentiated neurons.…”

Section: Introductionmentioning

confidence: 99%

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Gtf2i and Gtf2ird1 mutation are not sufficient to reproduce mouse phenotypes caused by the Williams Syndrome critical region

Kopp¹,

McCullough²,

Se³

et al. 2019

Preprint

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Williams syndrome is a neurodevelopmental disorder caused by a 1.5-1.8Mbp deletion on chromosome 7q11.23, affecting the copy number of 26-28 genes. Phenotypes of Williams syndrome include cardiovascular problems, craniofacial dysmorphology, deficits in visual spatial cognition, and a characteristic hypersocial personality. There are still no genes in the region that have been consistently linked to the cognitive and behavioral phenotypes, although human studies and mouse models have led to the current hypothesis that the general transcription factor 2 I family of genes, GTF2I and GTF2IRD1, are responsible. Here we test the hypothesis that these two transcription factors are sufficient to reproduce the phenotypes that are caused by deletion of the Williams syndrome critical region (WSCR). We compare a new mouse model with loss of function mutations in both Gtf2i and Gtf2ird1 to an established mouse model lacking the complete WSCR. We show that the complete deletion model has deficits across several behavioral domains including social communication, motor functioning, and conditioned fear that are not explained by loss of function mutations in Gtf2i and Gtf2ird1. Furthermore, transcriptome profiling of the hippocampus shows changes in synaptic genes in the complete deletion model that are not seen in the double mutants. Thus, we have thoroughly defined a set of molecular and behavioral consequences of complete WSCR deletion, and shown that other genes or combinations of genes are necessary to produce these phenotypic effects.

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Section: Resultsmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Gtf2i and Gtf2ird1 mutation are not sufficient to reproduce mouse phenotypes caused by the Williams Syndrome critical region

Kopp¹,

McCullough²,

Se³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Neurodevelopmental disorders are currently associated with cognitive dysfunctions, with the neocortex underlying high cognitive functions in humans. For this reason, cortical neuronal subtypes such as pyramidal glutamatergic cells have been predominantly used in vitro [ 15 , 17 , 28 , 29 , 46 ].…”

Section: Reconstruction Of Brain Circuitry Using Neural Transplants Gmentioning

confidence: 99%

Induced pluripotent stem cells as a tool to study brain circuits in autism-related disorders

Vitrac

Cloëz‐Tayarani

2018

Stem Cell Res Ther

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The mammalian brain is a very complex organ containing an estimated 200 billion cells in humans. Therefore, studying human brain development has become very challenging given all the data that are available from different approaches, notably genetic studies.Recent pluripotent stem cell methods have given rise to the possibility of modeling neurodevelopmental diseases associated with genetic defects. Fibroblasts from patients have been reprogrammed into pluripotent stem cells to derive appropriate neuronal lineages. They specifically include different subtypes of cortical neurons that are at the core of human-specific cognitive abilities. The use of neurons derived from induced pluripotent stem cells (iPSC) has led to deciphering convergent and pleiotropic neuronal synaptic phenotypes found in neurodevelopmental disorders such as autism spectrum disorders (ASD) and their associated syndromes. In addition to these initial studies, remarkable progress has been made in the field of stem cells, with the major objective of reproducing the in vivo maturation steps of human neurons. Recently, several studies have demonstrated the ability of human progenitors to respond to guidance cues and signals in vivo that can direct neurons to their appropriate sites of differentiation where they become fully mature neurons.We provide a brief overview on research using human iPSC in ASD and associated syndromes and on the current understanding of new theories using the re-implantation of neural precursors in mouse brain.

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Williams syndrome: reduced orienting to other’s eyes in a hypersocial phenotype

Kleberg

Riby

Fawcett

et al. 2022

J Autism Dev Disord

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Williams syndrome (WS) is a rare genetic condition associated with high sociability, intellectual disability, and social cognitive challenges. Attention to others’ eyes is crucial for social understanding. Orienting to, and from other’s eyes was studied in WS (n = 37, mean age = 23, age range 9–53). The WS group was compared to a typically developing comparison participants (n = 167) in stratified age groups from infancy to adulthood. Typically developing children and adults were quicker and more likely to orient to eyes than the mouth. This bias was absent in WS. The WS group had reduced peak saccadic velocities, indicating hypo-arousal. The current study indicates reduced orienting to others’ eyes in WS, which may affect social interaction skills.

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Modeling Williams syndrome with induced pluripotent stem cells

Cited by 12 publications

References 59 publications

Gtf2i and Gtf2ird1 mutation are not sufficient to reproduce mouse phenotypes caused by the Williams Syndrome critical region

Gtf2i and Gtf2ird1 mutation are not sufficient to reproduce mouse phenotypes caused by the Williams Syndrome critical region

Induced pluripotent stem cells as a tool to study brain circuits in autism-related disorders

Williams syndrome: reduced orienting to other’s eyes in a hypersocial phenotype

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