Genetic Screening Technique Reveals How Autism Mutations Impact Brain Cell Development in Organoids
A groundbreaking new genetic screening technique has shed light on how mutations associated with autism can alter the development of brain cells in organoids. The study, published in the journal Nature, aimed to identify vulnerable steps in brain development that are particularly susceptible to gene mutations linked to autism.
The research builds upon previous work by Jürgen Knoblich and his team at the Medical University of Vienna in Austria. In 2020, they developed a technique to screen genes associated with microcephaly for their ability to impair cell growth. Using CRISPR technology, the team introduced genetic mutations into human stem cells, which were then grown into organoids. Each stem cell contained a unique genetic barcode, allowing the researchers to track the accumulated mutations in each cell.
For the current study, the team used a similar approach to generate organoids with mutations in 36 genes strongly associated with autism. Each cell within the mosaic organoids carried a single mutation. This is the first time that such a large number of genes have been examined simultaneously in the same model, according to Flora Vaccarino, a professor of neuroscience at Yale University.
After four months of growth, the organoids consisted of thousands of cells with each specific mutation. The researchers then used single-cell RNA sequencing to measure the abundance of individual cell types. Analysis revealed that mutations in 24 of the 36 genes altered the ratio of excitatory neurons to inhibitory interneurons. Additionally, approximately one-third of the mutations reduced the number of intermediate progenitor cells, which are crucial for integrating information across brain regions.
The findings suggest that an imbalance of cell types may be a common factor in the development of autism spectrum disorder. One gene in particular, ARID1B, stood out as having a significant impact in the organoids. ARID1B mutations caused a greater number of cells to become oligodendrocyte precursors, which are responsible for generating the electrical insulation around neurons and have been linked to autism.
Interestingly, the study also examined organoids derived from two individuals with naturally occurring ARID1B mutations. These organoids demonstrated the same atypical increase in oligodendrocyte precursors as the CRISPR-engineered organoids, confirming the validity of the findings.
While the study focused on genes associated with transcriptional regulation, Knoblich notes that many other autism-related genes are involved in the formation and maintenance of connections between neurons. He believes that the versatile nature of the technique used in this study could be applied to examine other gene sets in future research.
According to Knoblich, the next step in validating these findings is to study more individuals with a range of other genetic mutations associated with autism. The ultimate goal is to better understand how these mutations impact brain development and potentially identify new therapeutic targets for autism spectrum disorder.