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Pathological priming causes developmental gene network heterochronicity in autistic subject-derived neurons
Open accessAbstract
Autism spectrum disorder (ASD) is thought to emerge during early cortical development. However, the exact developmental stages and associated molecular networks that prime disease propensity are elusive. To profile early neurodevelopmental alterations in ASD with macrocephaly, we monitored subject-derived induced pluripotent stem cells (iPSCs) throughout the recapitulation of cortical development. Our analysis revealed ASD-associated changes in the maturational sequence of early neuron development, involving temporal dysregulation of specific gene networks and morphological growth acceleration. The observed changes tracked back to a pathologically primed stage in neural stem cells (NSCs), reflected by altered chromatin accessibility. Concerted over-representation of network factors in control NSCs was sufficient to trigger ASD-like features, and circumventing the NSC stage by direct conversion of ASD iPSCs into induced neurons abolished ASD-associated phenotypes. Our findings identify heterochronic dynamics of a gene network that, while established earlier in development, contributes to subsequent neurodevelopmental aberrations in ASD.
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“Consistently, compared with gene expression signatures from bulk adult brain regions from the Allen BrainSpan dataset, both iNs and iPSC-iNs were most similar to prefrontal and frontal adult human cortex samples and less to other regions (Figure 7E; Mertens et al., 2015a; Schafer et al., 2019).”
From Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients (2021) · cites this paper as Schafer et al., 2019
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Metadata
- Authors
- Schafer, S. T., Paquola, A. C. M., Stern, S., Gosselin, D., Ku, M., Pena, M., Kuret, T. J. M., Liyanage, M., Mansour, A. A., Jaeger, B. N., Marchetto, M. C., Glass, C. K., Mertens, J., & Gage, F. H.
- Affiliations
- Salk Institute for Biological Studies (US)
- Centre hospitalier universitaire de Québec (CA)
- University of California San Diego (US)
- Corresponding author
- Gage, Fred H.
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2019-01-07
- Volume
- 22
- Issue
- 2
- Pages
- 243-255
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC6402576
- OpenAlex
- W2906812748
- Cited by
- 288
- References
- 71
- Citations by year
- 2026: 18 · 2025: 34 · 2024: 25 · 2023: 35 · 2022: 40 · 2021: 44 · 2020: 63 · 2019: 28
- FWCI
- 25.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG056306)
- National Institute of Mental Health (R01MH090258, R03MH115426, R01MH095741)
- National Cancer Institute (P30CA014195)
- National Institute of Neurological Disorders and Stroke (R01NS096170)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- autism spectrum disorder, heterochrony, cortical development, neural stem cells, induced neurons, induced pluripotent stem cells, chromatin accessibility, macrocephaly, iPSC-derived neurons
- MeSH terms
- Autism Spectrum Disorder, Humans, Nerve Net, Neurons, Gene Regulatory Networks, Inhibitory Postsynaptic Potentials, Induced Pluripotent Stem Cells, Neural Stem Cells
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