Development and Disease in a Dish: The Epigenetics of Neurodevelopmental Disorders

Abstract

Human neurodevelopmental disorders (NDDs) involve mutations in hundreds of individual genes, with over-representation in genes encoding proteins that alter chromatin structure to modulate gene expression. Here, we highlight efforts to model these NDDs through in vitro differentiation of patient-specific induced pluripotent stem cells into neurons. We discuss how epigenetic regulation controls normal cortical development, how mutations in several classes of epigenetic regulators contribute to NDDs, and approaches for modeling cortical development and function using both directed differentiation and formation of cerebral organoids. We explore successful applications of these models to study both syndromic and nonsyndromic NDDs and to define convergent mechanisms, addressing both the potential and challenges of using this approach to define cellular and molecular mechanisms that underlie NDDs.

Keywords::

• autism spectrum disorder
• cerebral cortex
• cerebral organoid
• chromatin
• epigenetic
• genetics
• induced pluripotent stem cell
• in vitro differentiation
• neurodevelopmental disorder
• neuron

Acknowledgements

The authors thank K Meganathan, D Baldridge, and A Clemens for constructive suggestions on the manuscript.

Financial & competing interests disclosure

This work was supported by grants to KL Kroll from the NIH (GM66815), the March of Dimes (#1-FY13–413), the American Epilepsy Society, the McDonnell Center for Cellular and Molecular Neurobiology at Washington University, and the Center for Regenerative Medicine at Washington University. This project was also supported by an NIGMS T32 training grant to EMA Lewis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

This work was supported by grants to KL Kroll from the NIH (GM66815), the March of Dimes (#1-FY13–413), the American Epilepsy Society, the McDonnell Center for Cellular and Molecular Neurobiology at Washington University, and the Center for Regenerative Medicine at Washington University. This project was also supported by an NIGMS T32 training grant to EMA Lewis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.