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

• Published in: Nature neuroscience Vol. 22; no. 2; pp. 243 - 255
• Main Authors: 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
• Language: English
• Published: New York Nature Publishing Group US 01.02.2019; Nature Publishing Group
• Subjects: 13; 13/100; 38; 38/39; 38/91; 631/378/1689/1373; 631/378/2571/1696; 631/532/2064/2158; Animal Genetics and Genomics; Autism; Autism Spectrum Disorder - genetics; Autism Spectrum Disorder - pathology; Autism Spectrum Disorder - physiopathology; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain; Care and treatment; Chromatin; Cortex; Developmental stages; Direct conversion; Gene expression; Gene Regulatory Networks; Genes; Humans; Induced Pluripotent Stem Cells - pathology; Inhibitory postsynaptic potentials; Inhibitory Postsynaptic Potentials - physiology; Macrocephaly; Nerve Net - physiopathology; Neural stem cells; Neural Stem Cells - pathology; Neurobiology; Neurons; Neurons - pathology; Neurons - physiology; Neurosciences; Pervasive developmental disorders; Phenotypes; Pluripotency; Priming; Risk factors; Stem cells
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/s41593-018-0295-x

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. Using a dynamic time-course approach to model developmental trajectories in autism spectrum disorder, Schafer et al. identified aberrant gene network dynamics as a part of an ongoing process that is primed early in development.