Modeling Smith-Lemli-Opitz syndrome with induced pluripotent stem cells reveals a causal role for Wnt/β-catenin defects in neuronal cholesterol synthesis phenotypes

Francis, Kevin; Ton, Amy N.; Yao, Xin; O'Halloran, Peter E; Wassif, Christopher A.; Malik, Nasir; Williams, Ian M.; Cluzeau, Céline; Trivedi, Niraj; Pavan, William J.; Cho, Wonhwa; Westphal, Heiner; Porter, Forbes D.

doi:10.1038/nm.4067

Cited by 53 publications

(64 citation statements)

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“…To validate our network model for applications to study diseases, we performed spatial network analyses using an iPSC disease model of Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive developmental disorder resulting from mutations in DHCR7 which produces pronounced neurological deficits 29 . Previous studies have shown accelerated differentiation of neural progenitors derived from patients with SLOS 22 , likely caused by decreased activity of the canonical Wnt/β-catenin signaling pathway in these cells.…”

Section: Resultsmentioning

confidence: 93%

“…Further, the higher number of neurons in SLOS cultures comprised a large number of ‘lone’ cells with high neurite extension. While the mechanisms underlying altered neural networks in SLOS are unclear, published findings related to cytoskeletal remodeling or diminished β-catenin signaling affecting cadherin function are possibilities 22,36 .…”

Section: Discussionmentioning

confidence: 99%

“…Neural stem cells were derived from two human iPSC lines, NCRM-5 and CWI 4F2, following published protocols 22 ( Supplementary Table 3 ). NSCs were cultured on dishes coated with Poly-L-Ornithine and Laminin, in media containing DMEM/F12 (Life Technologies), B27 without vitamin A (Life Technologies), 20 ng/mL EGF (Sigma), 20 ng/mL bFGF (Stemgent) and penicillin/streptomycin (Life Technologies).…”

Section: Methodsmentioning

confidence: 99%

“…Monolayer cultures of human stem cells capture many aspects of in vivo neural development, such as spatial and temporal features of cortical neurogenesis 19,20 . In addition, iPSC models have been used to study aberrant development in several neurodevelopmental disorders 21,22 . The ubiquity of stem cell differentiation protocols provides a unique opportunity to study the self-assembly of neural networks in a dish.…”

Section: Introductionmentioning

confidence: 99%

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Living Neural Networks: Dynamic Network Analysis of Developing Neural Progenitor Cells

Mahadevan

et al. 2016

Preprint

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12The architecture of the mammalian brain has been characterized through decades of innovation in the 13 field of network neuroscience. However, the assembly of the brain from progenitor cells is an immensely 14 complex process, and a quantitative understanding of how neural progenitor cells (NPCs) form neural 15 networks has proven elusive. Here, we introduce a method that integrates graph-theory with long-term 16 imaging of differentiating human NPCs to characterize the evolution of spatial and functional network 17 features in NPCs during the formation of neural networks in vitro. We find that the rise and fall in spatial 18 network efficiency is a characteristic feature of the transition from immature NPC networks to mature 19 neural networks. Furthermore, networks at intermediate stages of differentiation that display high spatial 20 network efficiency also show high levels of network-wide spontaneous electrical activity. These results 21 support the view that network-wide signaling in immature progenitor cells gives way to a hierarchical 22 form of communication in mature neural networks. We also leverage graph theory to study the spatial 23 features of individual cell types in developing cultures, uncovering spatial features of polarized 24 neuroepithelium. Finally, we employ our method to uncover aberrant network features in a 25 neurodevelopmental disorder using induced pluripotent stem cell (iPSC) models. The "Living Neural 26 Networks" method bridges the gap between developmental neurobiology and network neuroscience, and 27 offers insight into the relationship between developing and mature neural networks. 28 29 42 the fundamental architectural features of neural networks, no models have been available to study the 43 development of human neural networks from progenitor cells in a quantitative manner, nor have there 44 been tools to characterize the spatial and functional dynamics of network formation at the cellular level. 45 46 Cell-cell communication among neural progenitor cells (NPCs) is an essential aspect of human nervous 47 65 features of cortical neurogenesis 19,20 . In addition, iPSC models have been used to study aberrant 66 development in several neurodevelopmental disorders 21,22 . The ubiquity of stem cell differentiation 67 protocols provides a unique opportunity to study the self-assembly of neural networks in a dish. 69In this report, we introduce a method to study network features of developing human neural networks at 70 the global and single-cell levels. We use long-term imaging coupled with automated image analysis to 71 develop network representations of cell spatial topology and assign spatial coordinates to individual cells 72 (Figure 1). We use our method to demonstrate that two independent human NPC cell lines exhibit a 73 similar rise and fall in spatial network efficiency that characterizes the maturation of in vitro neural 74 networks. We demonstrate that high spatial network efficiencies at intermediate stages of neural 75 differentiation are linked with high levels of sp...

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Section: Resultsmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Living Neural Networks: Dynamic Network Analysis of Developing Neural Progenitor Cells

Mahadevan

et al. 2016

Preprint

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“…This study demonstrated that 7-DHC has a direct inhibitory effect on formation of a functionally active Wnt receptor complex. 38 Wnt signaling has been shown to regulate ephrin receptor expression ( EPHRA4 ), which was identified as an important gene in the PVS disease locus. 28,39 …”

Section: Discussion)mentioning

confidence: 99%

Pulmonary vein stenosis in patients with Smith-Lemli-Opitz syndrome

Prosnitz

Leopold

Irons

et al. 2017

Congenital Heart Disease

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Objective To describe a group of children with co-incident pulmonary vein stenosis and Smith-Lemli-Opitz syndrome and to generate hypotheses as to the shared pathogenesis of these disorders. Design Retrospective case series Patients Five subjects in a pulmonary vein stenosis cohort of 170 subjects were diagnosed with Smith-Lemli-Opitz syndrome soon after birth. Results All five cases were diagnosed with Smith-Lemli-Opitz syndrome within six weeks of life, with no prior family history of either disorder. All cases had pathologically elevated 7-dehydrocholesterol levels and two of the five cases had previously reported pathogenic 7-dehydrocholesterol reductase mutations. Smith-Lemli-Opitz syndrome severity scores ranged from mild to classical (2–7). Gestational age at birth ranged from 35 to 39 weeks. Four of the cases were male by karyotype. Pulmonary vein stenosis was diagnosed in all cases within two months of life, earlier than most published cohorts. All cases progressed to bilateral disease and three cases developed atresia of at least one vein. Despite catheter and surgical interventions, all subjects’ pulmonary vein stenosis rapidly recurred and progressed. Three of the subjects died, at 2 months, 3 months, and 11 months. Survival at 16 months after diagnosis was 43%. Conclusions Patients with pulmonary vein stenosis who have a suggestive syndromic presentation should be screened for Smith-Lemli-Opitz syndrome with easily obtainable serum sterol tests. Echocardiograms should be obtained in all newly diagnosed patients with Smith-Lemli-Opitz syndrome, with a low threshold for repeating the study if new respiratory symptoms of uncertain etiology arise. Further studies into the pathophysiology of pulmonary vein stenosis should consider the role of cholesterol-based signaling pathways in the promotion of intimal proliferation.

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Spontaneously regressing brain lesions in Smith–Lemli–Opitz syndrome

Dang

Baker²,

Warren

et al. 2017

American J of Med Genetics Pt A

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Smith-Lemli-Opitz syndrome (SLOS) is a metabolic disorder caused by an inborn error of cholesterol synthesis that affects the development of many organ systems. Malformations in the central nervous system typically involve midline structures and reflect abnormal growth and differentiation of neurons and supporting cells. Despite these defects in central nervous system development, brain tumor formation has only rarely been reported in association with SLOS. We present three individuals with SLOS and lesions in the basal ganglia or brainstem detected by MRI that were concerning for tumor formation. However, the individuals' clinical and neurological course remained stable, and the lesions regressed after several years. These lesions have similarities to spongiotic changes observed in individuals with neurofibromatosis type 1 (NF1). Notably, impaired activity of small GTPases is present in both SLOS and NF1, perhaps giving mechanistic insight into the formation of these lesions.

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Modeling Smith-Lemli-Opitz syndrome with induced pluripotent stem cells reveals a causal role for Wnt/β-catenin defects in neuronal cholesterol synthesis phenotypes

Cited by 53 publications

References 54 publications

Living Neural Networks: Dynamic Network Analysis of Developing Neural Progenitor Cells

Living Neural Networks: Dynamic Network Analysis of Developing Neural Progenitor Cells

Pulmonary vein stenosis in patients with Smith-Lemli-Opitz syndrome

Spontaneously regressing brain lesions in Smith–Lemli–Opitz syndrome

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