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Nat Neurosci. 2019 Feb;22(2):243-255. doi: 10.1038/s41593-018-0295-x. Epub 2019 Jan 7.

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

Author information

1
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.
2
Lieber Institute for Brain Development, Baltimore, MD, USA.
3
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
4
Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec, Canada.
5
Next Generation Sequencing Core, The Salk Institute for Biological Studies, La Jolla, CA, USA.
6
Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
7
Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, Zurich, Switzerland.
8
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
9
Department of Genomics, Stem Cell Biology and Regenerative Medicine, Institute of Molecular Biology & CMBI, University of Innsbruck, Innsbruck, Austria.
10
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA. gage@salk.edu.

Abstract

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.

PMID:
30617258
PMCID:
PMC6402576
DOI:
10.1038/s41593-018-0295-x
[Indexed for MEDLINE]
Free PMC Article

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