Organoids open window into development of human forebrain

Brain region-specific organoids have allowed researchers to peer inside the complex programming of human forebrain development, a process once inaccessible to molecular study. The results bring new insight into the gene-regulatory dynamics of human forebrain development during previously inaccessible stages and reveal transcriptional signatures of neuropsychiatric disorders. The development of the human forebrain – the region of the brain that houses many of our most uniquely human traits and cognitive abilities – is a complex process. Through a lengthy series of precisely orchestrated cellular and molecular events, cells differentiate and organize into the circuits that store memories, allow conscious thought and create our emotions. Epigenetic gene regulation is known to play a crucial role in guiding the forebrain development. Environmental or genetic disruptions to the highly synchronized process can cause severe neurodevelopmental diseases. However, due to the challenges of working with developing human brain tissues, much of what is known stems mainly from animal models. As a result, our understanding of the molecular programs that underpin the precise and dynamic processes in the human brain is limited, particularly during critical developmental periods. To address this, Alexandro Trevino and colleagues developed 3D organoid models of human forebrain development to study chromatin accessibility and gene expression in specific cells over several critical developmental stages. The in vitro approach allowed Trevino et al. to identify transcription factors that regulate cortical development. Furthermore, the authors were able to map genetic risk for neurodevelopmental disease to specific cell types during development.

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