Neuronal defects in a human cellular model of 22q11.2 deletion syndrome

Khan, Themasap A.; Revah, Omer; Gordon, Aaron; Yoon, Se-Jin; Krawisz, Anna K; Goold, Carleton P.; Sun, Yishan; Kim, Chul Hoon; Tian, Yuan; Li, Min-Yin; Schaepe, Julia; Ikeda, Kazuya; Amin, Neal D.; Sakai, Noriaki; Yazawa, Masayuki; Kushan, Leila; Nishino, Seiji; Porteus, Matthew H.; Rapoport, Judith L.; Bernstein, Jonathan A.; O’Hara, Ruth; Bearden, Carrie E.; Hallmayer, Joachim; Huguenard, John R.; Geschwind, Daniel H.; Dolmetsch, Ricardo; Paşca, Sergiu P.

doi:10.1038/s41591-020-1043-9

Cited by 123 publications

(99 citation statements)

References 74 publications

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“…2013 ). Human induced pluripotent stem cell–derived neurons with hemizygous DGCR8 loss also show changes in calcium signaling and excitability ( Khan et al. 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Prioritizing Genetic Contributors to Cortical Alterations in 22q11.2 Deletion Syndrome Using Imaging Transcriptomics

et al. 2021

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22q11.2 deletion syndrome (22q11DS) results from a hemizygous deletion that typically spans 46 protein-coding genes and is associated with widespread alterations in brain morphology. The specific genetic mechanisms underlying these alterations remain unclear. In the 22q11.2 ENIGMA Working Group, we characterized cortical alterations in individuals with 22q11DS (n = 232) versus healthy individuals (n = 290) and conducted spatial convergence analyses using gene expression data from the Allen Human Brain Atlas to prioritize individual genes that may contribute to altered surface area (SA) and cortical thickness (CT) in 22q11DS. Total SA was reduced in 22q11DS (Z-score deviance = −1.04), with prominent reductions in midline posterior and lateral association regions. Mean CT was thicker in 22q11DS (Z-score deviance = +0.64), with focal thinning in a subset of regions. Regional expression of DGCR8 was robustly associated with regional severity of SA deviance in 22q11DS; AIFM3 was also associated with SA deviance. Conversely, P2RX6 was associated with CT deviance. Exploratory analysis of gene targets of microRNAs previously identified as down-regulated due to DGCR8 deficiency suggested that DGCR8 haploinsufficiency may contribute to altered corticogenesis in 22q11DS by disrupting cell cycle modulation. These findings demonstrate the utility of combining neuroanatomic and transcriptomic datasets to derive molecular insights into complex, multigene copy number variants.

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“…2013 ). Human induced pluripotent stem cell–derived neurons with hemizygous DGCR8 loss also show changes in calcium signaling and excitability ( Khan et al. 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Prioritizing Genetic Contributors to Cortical Alterations in 22q11.2 Deletion Syndrome Using Imaging Transcriptomics

et al. 2021

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“…Cerebral organoids are three-dimensional (3D) structures reminiscent of human brain regions, including the cerebral cortex and subventricular zone. Recently, several independent studies have established cerebral organoids to clarify the pathogenesis of microcephaly, autism, Miller-Dieker syndrome and other neurodevelopmental disorders (14,15,20,21,(25)(26)(27)(28)(29), but there have been no reports on the pathological mechanism underlying delayed cortical development in DS. Among the protein-coding genes in HSA21 (human chromosome 21), Down's syndrome cell adhesion molecule (DSCAM) encodes a cell adhesion molecule involved in neuronal generation, maturation, dendrite morphology and neuronal wiring (30) (31), which is important for brain development.…”

Section: Introductionmentioning

confidence: 99%

DSCAM/PAK1 pathway suppression reverses neurogenesis deficits in iPSC-derived cerebral organoids from patients with Down syndrome

Tang¹,

Xu²,

Wang

et al. 2021

Journal of Clinical Investigation

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Down syndrome (DS), caused by trisomy of chromosome 21, occurs in 1 of every 800 live births.Early defects in cortical development likely account for the cognitive impairments in DS, although the underlying molecular mechanism remains elusive. Here, we performed histological assays and unbiased single-cell RNA sequencing (scRNA-seq) analysis on cerebral organoids derived from four euploid cell lines and from induced pluripotent stem cells (iPSCs) from three individuals with trisomy 21 to explore cell type-specific abnormalities associated with DS during early brain development. We found that neurogenesis was significantly affected based on diminished proliferation and decreased expression of layer II and IV markers in cortical neurons in the subcortical regions; this may be responsible for the reduced size of the organoids. Furthermore, suppression of the DSCAM-PAK1 pathway which showed enhanced activities in DS) via CRISPR/Cas9, CRISPRi or small-molecule inhibitor treatment reverses abnormal neurogenesis, thereby increasing the size of organoids derived from DS iPSCs. Our study demonstrated that 3D cortical organoids developed in vitro are a valuable model of DS and provided a direct link between dysregulation of the DSCAM-PAK1 pathway and developmental brain defects in DS.

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“…Specifically, CRISPR system has been used to achieve gene knock-out or genetic mutation repair to facilitate disease modeling (Table 1). Organoids generated from genome-edited patient-specific iPSCs were used to evaluate genetic contributions to diseases such as DKC1 mutation in dyskeratosis congenita, 112 22q11 deletion in neuropsychiatric disease, 113 RPGR mutations in retinitis pigmentosa, 114 roles of podocalyxin, PKD1 and PKD2 in kidney development and polycystic kidney disease, 115 CFTR in cystic fibrosis, 116 TSC2 in tuberous sclerosis complex, 117 as well as IFT140 variants in nephronophthisis-related ciliopathies. 118 3D organoid culture has also seen increasing applications in cancer research.…”

Section: Applications Of Genome Editing In Human Organoid Studiesmentioning

confidence: 99%

Convergence of human pluripotent stem cell, organoid, and genome editing technologies

Wang

Jang

2021

Exp Biol Med (Maywood)

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The last decade has seen many exciting technological breakthroughs that greatly expanded the toolboxes for biological and biomedical research, yet few have had more impact than induced pluripotent stem cells and modern-day genome editing. These technologies are providing unprecedented opportunities to improve physiological relevance of experimental models, further our understanding of developmental processes, and develop novel therapies. One of the research areas that benefit greatly from these technological advances is the three-dimensional human organoid culture systems that resemble human tissues morphologically and physiologically. Here we summarize the development of human pluripotent stem cells and their differentiation through organoid formation. We further discuss how genetic modifications, genome editing in particular, were applied to answer basic biological and biomedical questions using organoid cultures of both somatic and pluripotent stem cell origins. Finally, we discuss the potential challenges of applying human pluripotent stem cell and organoid technologies for safety and efficiency evaluation of emerging genome editing tools.

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Neuronal defects in a human cellular model of 22q11.2 deletion syndrome

Cited by 123 publications

References 74 publications

Prioritizing Genetic Contributors to Cortical Alterations in 22q11.2 Deletion Syndrome Using Imaging Transcriptomics

Prioritizing Genetic Contributors to Cortical Alterations in 22q11.2 Deletion Syndrome Using Imaging Transcriptomics

DSCAM/PAK1 pathway suppression reverses neurogenesis deficits in iPSC-derived cerebral organoids from patients with Down syndrome

Convergence of human pluripotent stem cell, organoid, and genome editing technologies

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