Pathological priming causes developmental gene network heterochronicity in autistic subject-derived neurons

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-d...

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Veröffentlicht in:Nature neuroscience Jg. 22; H. 2; S. 243 - 255
Hauptverfasser: Schafer, Simon T, Paquola, Apua C M, Stern, Shani, Gosselin, David, Ku, Manching, Pena, Monique, Kuret, Thomas J M, Liyanage, Marvin, Mansour, Abed AlFatah, Jaeger, Baptiste N, Marchetto, Maria C, Glass, Christopher K, Mertens, Jerome, Gage, Fred H
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Nature Publishing Group 01.02.2019
Schlagworte:
Autism
Autism Spectrum Disorder - genetics
Autism Spectrum Disorder - pathology
Autism Spectrum Disorder - physiopathology
Chromatin
Cortex
Developmental stages
Direct conversion
Gene Regulatory Networks
Humans
Induced Pluripotent Stem Cells - pathology
Inhibitory postsynaptic potentials
Inhibitory Postsynaptic Potentials - physiology
Macrocephaly
Nerve Net - physiopathology
Neural stem cells
Neural Stem Cells - pathology
Neurons
Neurons - pathology
Neurons - physiology
Phenotypes
Pluripotency
Priming
Stem cells
ISSN:1097-6256, 1546-1726, 1546-1726
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
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ISSN:1097-6256
1546-1726
1546-1726
DOI:10.1038/s41593-018-0295-x