Thanks to an incredible effort and an amazing team, especially my co-lead authors Bruna Paulsen, Silvia Velasco and Martina Pigoni, our paper is out in Nature! Great work has been done to shine light on the genetics of autism spectrum disorder, and we know that your risk of ASD is influenced by variants in *hundreds* of genes. We focused in on 3 of them - SUV420H1 / KMT5B, ARID1B, and CHD8. These genes influence your risk of ASD, but why? How do they affect the brain during development? To find out, we leveraged a reproducible lab-grown model of human cortical brain development. My colleagues created heterozygous mutations in each one of these three genes in stem cell lines, and grew them along with isogenic controls, over several months, into brain organoids. The organoids grow the same kinds of cells that would appear during human cortical development. We used single-cell RNA sequencing (& more) to compare the mutated and control organoids. We found that mutated ones grow certain cell types at different times. In this figure, organoids with SUV mutations have accelerated development of Immature Deep Layer Projection Neurons. Sometimes the direction was the opposite – i.e. in ARID1B mutated organoids, there was a *delayed* differentiation of those same neurons. But the types of cells where we saw a shift was the same across all three genes: deep layer projection neurons, and early GABAergic neurons. One major finding here- although these effects were consistent, which cell line you use for organoids matters for how big the effect is. A lot! This means that researchers need to consider the cell lines they use – and how many! – when drawing conclusions about complex disorders. We’re left wondering what differing speed of neuron development affects downstream. For the first clue, Sung Min Yang used calcium imaging to look at the neuron’s activity in the organoids, and found changes in circuit activity in SUV420H1 mutants. Tantalizing results… This was a huge project with SO many moving parts & great teamwork! It started years before I joined the lab and I'm so glad to see it out in the world.
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AuthorAmanda Kedaigle's work in the Broad Institute focuses on leveraging brand new biological data modalities to study novel models of human brain development. Archives
February 2022
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