Editors' ChoiceAutism

Brain development in autism: Timing is everything

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Science Translational Medicine  23 Jan 2019:
Vol. 11, Issue 476, eaaw5314
DOI: 10.1126/scitranslmed.aaw5314

Abstract

Gene network analysis in stem cell–derived cortical neurons from individuals with autism reveals accelerated neuronal maturation.

Autism is regarded as a disorder of brain development, but precisely when the neurodevelopmental program goes awry and in which cell types remain key unanswered questions. These questions have now been addressed in a study by Schafer et al., using human induced pluripotent stem cells (hiPSCs) from eight male individuals with autism spectrum disorder (ASD) plus macrocephaly, and five male controls. The authors differentiated the hiPSCs into neural stem cells (NSCs), which can still multiply, and systematically mapped gene expression over the next two weeks as these cells matured into cortical neurons. Network analysis revealed various “modules” of co-expressed genes, three of which (TM1-3) showed a temporal pattern that reflected normal development. One of these, TM1, which included many autism risk genes along with neural development genes, showed an accelerated pattern of expression in the ASD group compared with controls. Indeed, the ASD neurons themselves also exhibited an accelerated pattern of growth, developing longer, more complex branches, and when grown as three-dimensional organoids had a thicker immature cortex. The authors tracked back the first signs of accelerated cortical development to early differentiation. Looking even earlier, they discovered that NSCs from autistic subjects failed to show the down-regulation of TM1 genes that was seen in the controls, suggesting a “primed” state in these cells. Interestingly, the ASD NSCs also had a different pattern of chromatin accessibility, with genes from the TM1 group particularly affected, potentially linking these findings to the known association of chromatin remodeling genes with autism risk.

To really gauge the impact of the premature expression of TM1 genes in cortical development, the authors took several of the top hit TM1 genes and overexpressed them (alone or in combination) in control NSCs. Sure enough, they were able to recapitulate the accelerated neuronal growth seen in the autism group. The authors then took advantage of a recent technique to generate neurons rapidly from stem cells by “direct differentiation” using forced expression of the gene, neurogenin2. This “skips over” the NSC stage, thereby bypassing the stage when the first subtle gene expression changes are seen. Strikingly, this rescued both the accelerated genetic program and neuronal growth patterns.

This study harnesses the power of using human stem cell–derived neurons to probe exactly how the neurodevelopmental program is altered in autism. Although it includes only eight affected individuals, this is a large number for studies involving hiPSCs. Importantly, by focusing on idiopathic autism—rather than a specific high penetrance gene—it allows us to begin to tease apart convergent mechanisms underlying this complex disorder.

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