Direct Reprogramming of Human Neurons Identifies MARCKSL1 as a Pathogenic Mediator of Valproic Acid-Induced Teratogenicity

Chanda, Soham; Ang, Cheen Euong; Lee, Qian Yi; Ghebrial, Michael; Haag, Daniel; Shibuya, Yohei; Wernig, Marius; Südhof, Thomas C.

doi:10.1016/j.stem.2019.04.021

Cited by 46 publications

(47 citation statements)

References 59 publications

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“…Genes with fold change >1.5 and Benjamini-Hochberg corrected P <0.1 were deemed as DE. To assess the overlap of VPA response in neuronal and microglia, we compared the DE genes in microglia with the reported DE genes in neurons in response to VPA treatment (Chanda et al, 2019) (Fig 4F). To identify the group level response of broadly-expressed and brain-specific rASD genes, we conducted GSEA in each transcriptomic sample using the Wilcoxon-Mann-Whitney test.…”

Section: Analysis Of Microglia Vpa Gene Expression Datamentioning

confidence: 99%

Autism genetics perturb prenatal neurodevelopment through a hierarchy of broadly-expressed and brain-specific genes

Gazestani¹,

Chiang²,

Courchesne³

et al. 2020

Preprint

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Numerous genes are associated with autism spectrum disorder (ASD); however, it remains unclear how most ASD risk genes influence neurodevelopment and result in similar traits. Recent genetic models of complex traits suggest non-tissue-specific genes converge on core disease genes; so we analyzed ASD genetics in this context. We found ASD risk genes partition cleanly into broadly-expressed and brain-specific genes. The two groups show sequential roles during neurodevelopment with broadly-expressed genes modulating chromatin remodeling, proliferation, and cell fate, while brain-specific risk genes are involved in neural maturation and synapse functioning. Broadly-expressed risk genes converge onto brain-specific risk genes and core neurodevelopmental genes through regulatory networks including PI3K/AKT, RAS/ERK, and WNT/ -catenin signaling pathways. Broadly-expressed and brain-specific risk genes show unique properties, wherein the broadly-expressed risk gene network is expressed prenatally and conserved in non-neuronal cells like microglia. However, the brain-specific gene network expression is limited to excitatory and inhibitory neurons, spanning prenatal to adulthood. Furthermore, the two groups are linked differently to comorbidities associated with ASD. Collectively, we describe here the organization of the genetic architecture of ASD as a hierarchy of broadlyexpressed and brain-specific genes that disrupt successive stages of core neurodevelopmental processes.Recent studies present an alternate model of complex traits where the functional impact of genetic aberrations propagates through gene regulatory networks to converge on downstream core processes related to the trait (Boyle et al., 2017;Califano and Alvarez, 2017;Courchesne et al., 2020;Gazestani et al., 2019;Iakoucheva et al., 2019;Liu et al., 2019). In contrast to the single-group rASD network model, if the polygenic and omnigenic models are relevant to ASD, they would suggest that many risk genes are not necessarily part of underlying neural mechanisms in ASD. Rather many rASD genes would be broadly-expressed across many tissues, but regulate core neurodevelopmental processes underlying ASD (Boyle et al., 2017;Califano and Alvarez, 2017;Courchesne et al., 2020;Gazestani et al., 2019). Moreover, by emphasizing the gene regulatory networks, these alternative models suggest that, to the extent that the gene regulatory networks are preserved, the dysregulation could also be reflected in non-neuronal cells . Supporting these ideas, many rASD genes are broadly-expressed across tissues and strongly enriched for gene expression regulators such as chromatin remodelers, transcription factors, and modulators of signaling pathways (Courchesne et al., 2020;Courchesne et al., 2019;Werling et al., 2020). Similarly, genome wide association studies (GWAS) and whole genome sequencing both highlight the important role of broadly functional eQTLs and gene regulatory networks in ASD liability (Brandler et al., 2018;Courchesne et al., 2020;Grove et al., 2019).The fundamen...

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Section: Analysis Of Microglia Vpa Gene Expression Datamentioning

confidence: 99%

Autism genetics perturb prenatal neurodevelopment through a hierarchy of broadly-expressed and brain-specific genes

Gazestani¹,

Chiang²,

Courchesne³

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…This approach allowed the generation of an almost 100% pure and homogeneous excitatory neuronal population from both human embryonic stem cells (hESCs) and hiPSCs which were electrophysiologically active and form synapses both in vitro and when transplanted into in vivo models [ 31 ]. In addition, this approach is valid for disease modeling and for assessing the deleterious mechanisms of teratogenic drugs [ 32 ]. Due to its robustness and efficiency, this approach has been widely used as a method to generate cortical neurons for disease modeling, as will be detailed below.…”

Section: Hipsc-derived Neurons For Ad Modeling and Platform For Scmentioning

confidence: 99%

Human Pluripotent Stem Cell-Derived Neural Cells as a Relevant Platform for Drug Screening in Alzheimer’s Disease

García-León

Cáceres-Palomo

Sánchez-Mejías

et al. 2020

IJMS

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Extracellular amyloid-beta deposition and intraneuronal Tau-laden neurofibrillary tangles are prime features of Alzheimer’s disease (AD). The pathology of AD is very complex and still not fully understood, since different neural cell types are involved in the disease. Although neuronal function is clearly deteriorated in AD patients, recently, an increasing number of evidences have pointed towards glial cell dysfunction as one of the main causative phenomena implicated in AD pathogenesis. The complex disease pathology together with the lack of reliable disease models have precluded the development of effective therapies able to counteract disease progression. The discovery and implementation of human pluripotent stem cell technology represents an important opportunity in this field, as this system allows the generation of patient-derived cells to be used for disease modeling and therapeutic target identification and as a platform to be employed in drug discovery programs. In this review, we discuss the current studies using human pluripotent stem cells focused on AD, providing convincing evidences that this system is an excellent opportunity to advance in the comprehension of AD pathology, which will be translated to the development of the still missing effective therapies.

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“…Indeed, a human iN cell type, instead of primary neuronal cells, was previously applied to in vitro drug treatment experiments. 48) Additionally, several directly induced neuronal and skeletal muscle cell types from patients with various diseases have been reported. 45)-47),104),105),207) Direct reprogramming technology has the potential to change the pharmaceutical industry.…”

Section: 2mentioning

confidence: 99%

Direct cell-fate conversion of somatic cells: Toward regenerative medicine and industries

Horisawa

Suzuki

2020

Proc. Jpn. Acad., Ser. B

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Cells of multicellular organisms have diverse characteristics despite having the same genetic identity. The distinctive phenotype of each cell is determined by molecular mechanisms such as epigenetic changes that occur throughout the lifetime of an individual. Recently, technologies that enable modification of the fate of somatic cells have been developed, and the number of studies using these technologies has increased drastically in the last decade. Various cell types, including neuronal cells, cardiomyocytes, and hepatocytes, have been generated using these technologies. Although most direct reprogramming methods employ forced transduction of a defined sets of transcription factors to reprogram cells in a manner similar to induced pluripotent cell technology, many other strategies, such as methods utilizing chemical compounds and microRNAs to change the fate of somatic cells, have also been developed. In this review, we summarize transcription factor-based reprogramming and various other reprogramming methods. Additionally, we describe the various industrial applications of direct reprogramming technologies.

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Direct Reprogramming of Human Neurons Identifies MARCKSL1 as a Pathogenic Mediator of Valproic Acid-Induced Teratogenicity

Cited by 46 publications

References 59 publications

Autism genetics perturb prenatal neurodevelopment through a hierarchy of broadly-expressed and brain-specific genes

Autism genetics perturb prenatal neurodevelopment through a hierarchy of broadly-expressed and brain-specific genes

Human Pluripotent Stem Cell-Derived Neural Cells as a Relevant Platform for Drug Screening in Alzheimer’s Disease

Direct cell-fate conversion of somatic cells: Toward regenerative medicine and industries

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