Uncovering True Cellular Phenotypes: Using Induced Pluripotent Stem Cell-Derived Neurons to Study Early Insults in Neurodevelopmental Disorders

Fink, James J.; Levine, Eric S.

doi:10.3389/fneur.2018.00237

Cited by 21 publications

(13 citation statements)

References 160 publications

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“…Compared to monolayer neuronal cultures, brain organoids have the ability to foster even more complex cell interactions that stimulate cellular maturation, better recapitulating potential pathological cascades (Logan et al, 2019). Both 2D iPSC-derived neuronal cultures and 3D brain organoids have already successfully been used for the study of several neurodevelopmental disorders to identify disease mechanisms and potential new therapeutic targets (Fink and Levine, 2018;Russo et al, 2019). To date, no iPSC-derived neuronal model for KCNQ2-E has been reported in the literature yet.…”

Section: Further Perspectivesmentioning

confidence: 99%

The Role of Kv7.2 in Neurodevelopment: Insights and Gaps in Our Understanding

et al. 2020

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Kv7.2 subunits encoded by the KCNQ2 gene constitute a critical molecular component of the M-current, a subthreshold voltage-gated potassium current controlling neuronal excitability by dampening repetitive action potential firing. Pathogenic loss-of-function variants in KCNQ2 have been linked to epilepsy since 1998, and there is ample functional evidence showing that dysfunction of the channel indeed results in neuronal hyperexcitability. The recent description of individuals with severe developmental delay with or without seizures due to pathogenic variants in KCNQ2 (KCNQ2-encephalopathy) reveals that Kv7.2 channels also have an important role in neurodevelopment. Kv7.2 channels are expressed already very early in the developing brain when key developmental processes such as proliferation, differentiation, and synaptogenesis play a crucial role in brain morphogenesis and maturation. In this review, we will discuss the available evidence for a role of Kv7.2 channels in these neurodevelopmental processes, focusing in particular on insights derived from KCNQ2related human phenotypes, from the spatio-temporal expression of Kv7.2 and other Kv7 family member, and from cellular and rodent models, highlighting critical gaps and research strategies to be implemented in the future. Lastly, we propose a model which divides the M-current activity in three different developmental stages, correlating with the cell characteristics during these particular periods in neuronal development, and how this can be linked with KCNQ2-related disorders. Understanding these mechanisms can create opportunities for new targeted therapies for KCNQ2-encephalopathy.

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Section: Further Perspectivesmentioning

confidence: 99%

The Role of Kv7.2 in Neurodevelopment: Insights and Gaps in Our Understanding

et al. 2020

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“…Our finding of the majority of dysregulated genes to be in excitatory neurons is particularly intriguing. Excitatory/inhibitory imbalance in neuronal communication in ASD is well supported by studies in animal [48][49][50] and in vitro models derived from human tissue [55]. Though whether this imbalance is causal or compensatory remains to be resolved.…”

Section: Discussionmentioning

confidence: 97%

Identification of amygdala-expressed genes associated with autism spectrum disorder

et al. 2020

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Background: Studies of individuals with autism spectrum disorder (ASD) have revealed a strong multigenic basis with the identification of hundreds of ASD susceptibility genes. ASD is characterized by social deficits and a range of other phenotypes, implicating complex genetics and involvement of a variety of brain regions. However, how mutations and mis-expression of select gene sets are associated with the behavioral components of ASD remains unknown. We reasoned that for genes to be associated with ASD core behaviors they must be: (1) expressed in brain regions relevant to ASD social behaviors and (2) expressed during the ASD susceptible window of brain development. Methods: Focusing on the amygdala, a brain region whose dysfunction has been highly implicated in the social component of ASD, we mined publicly available gene expression databases to identify ASD-susceptibility genes expressed during human and mouse amygdala development. We found that a large cohort of known ASD susceptibility genes is expressed in the developing human and mouse amygdala. We further performed analysis of single-nucleus RNA-seq (snRNA-seq) data from microdissected amygdala tissue from five ASD and five control human postmortem brains ranging in age from 4 to 20 years to elucidate cell type specificity of amygdalaexpressed genes and their dysregulation in ASD. Results: Our analyses revealed that of the high-ranking ASD susceptibility genes, 80 are expressed in both human and mouse amygdala during fetal to early postnatal stages of development. Our human snRNA-seq analyses revealed cohorts of genes with altered expression in the ASD amygdala postnatally, especially within excitatory neurons, with dysregulated expression of seven genes predicted from our datamining pipeline. Limitations: We were limited by the ages for which we were able to obtain human tissue; therefore, the results from our datamining pipeline approach will require validation, to the extent possible, in human tissue from earlier developmental stages. Conclusions: Our pipeline narrows down the number of amygdala-expressed genes possibly involved in the social pathophysiology of ASD. Our human single-nucleus gene expression analyses revealed that ASD is characterized by changes in gene expression in specific cell types in the early postnatal amygdala.

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“…Impairment in synaptic structure and integrated function has been pointed out as common pathophysiology across NDDs [ 56 ]. Synaptic dysfunction and decreased excitability of RSTS iNeurons may contribute to cognitive impairment of the patients [ 24 ] as shown for iNeurons of patients with Rett syndrome [ 29 , 57 ] and idiopathic autism [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Analysis of iPSC-Derived Neurons from Rubinstein-Taybi Patients Reveals Deficits in Neuronal Differentiation

et al. 2020

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Rubinstein-Taybi syndrome (RSTS) is a rare multisystem developmental disorder with moderate to severe intellectual disability caused by heterozygous mutations of either CREBBP or EP300 genes encoding CBP/p300 chromatin regulators. We explored the gene programs and processes underlying the morphological and functional alterations shown by iPSC-derived neurons modeling RSTS to bridge the molecular changes resulting from defective CBP/p300 to cognitive impairment. By global transcriptome analysis, we compared the differentially expressed genes (DEGs) marking the transition from iPSC-derived neural progenitors to cortical neurons (iNeurons) of five RSTS patients carrying private CREBBP/EP300 mutations and manifesting differently graded neurocognitive signs with those of four healthy controls. Our data shows a defective and altered neuroprogenitor to neuron transcriptional program in the cells from RSTS patients. First, transcriptional regulation is weaker in RSTS as less genes than in controls are modulated, including genes of key processes of mature functional neurons, such as those for voltage-gated channels and neurotransmitters and their receptors. Second, regulation is subverted as genes acting at pre-terminal stages of neural differentiation in cell polarity and adhesive functions (members of the cadherin family) and axon extension/guidance (members of the semaphorins and SLIT receptors families) are improperly upregulated. Impairment or delay of RSTS neuronal differentiation program is also evidenced by decreased modulation of the overall number of neural differentiation markers, significantly impacting the initial and final stages of the differentiation cascade. Last, extensive downregulation of genes for RNA/DNA metabolic processes confirms that RSTS is a global transcription disorder, consistent with a syndrome driven by chromatin dysregulation. Interestingly, the morphological and functional alterations we have previously appointed as biomarkers of RSTS iNeurons provide functional support to the herein designed transcriptome profile pointing to key dysregulated neuronal genes as main contributors to patients’ cognitive deficit. The impact of RSTS transcriptome may go beyond RSTS as comparison of dysregulated genes across modeled neurodevelopmental disorders could unveil convergent genes of cognitive impairment. Electronic supplementary material The online version of this article (10.1007/s12035-020-01983-6) contains supplementary material, which is available to authorized users.

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Uncovering True Cellular Phenotypes: Using Induced Pluripotent Stem Cell-Derived Neurons to Study Early Insults in Neurodevelopmental Disorders

Cited by 21 publications

References 160 publications

The Role of Kv7.2 in Neurodevelopment: Insights and Gaps in Our Understanding

The Role of Kv7.2 in Neurodevelopment: Insights and Gaps in Our Understanding

Identification of amygdala-expressed genes associated with autism spectrum disorder

Transcriptome Analysis of iPSC-Derived Neurons from Rubinstein-Taybi Patients Reveals Deficits in Neuronal Differentiation

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