Organoids bring new insight into human brain development and disease

Expansion of the human brain, specifically the forebrain, is a remarkable evolutionary process underpinning advanced cognitive and motor tasks that are the prerogative of humans. The unique nature of this developmental process makes animal models unsuitable for understanding aspects of human brain development and disease that are distinctly human. The emergence of pluripotent stem cell-derived organoids represents a significant advance in modeling human brain development in vitro and provides an invaluable opportunity to investigate cellular and molecular processes underlying brain diseases. However, the application of brain organoids to understand brain diseases has been impeded by the low reproducibility and complexity of these models. Mutations in epigenetic regulators are often found in neurodevelopmental disorders presenting increased brain size (megalencephaly) and intellectual disability, indicating that the establishment and maintenance of precise epigenetic states is fundamental for normal brain growth, development, and function. By leveraging highly reproducibly forebrain organoid models and multiomics, imaging and electrophysiolgical approaches, we investigated how mutations in selected epigenetic modifiers contribute to the pathogenesis of neurodevelopmental disorders. By uncovering cellular and molecular mechanisms behind epigenetic dysfunction during neurodevelopment,our work contributes to shed light on the link between abnormal brain growth and neurocognitive dysfunction in neurodevelopmental disorders, to ultimately identify new therapeutic interventions for these conditions. None