Mutations in a set of 35 genes linked to autism affect both neurons and glial cells in developing mice, according to a study published today. The study is the first to screen multiple autism-gene mutations, one by one, in living mice and analyze their effects in individual brain cells.
About 100 genes have been strongly linked to autism, and sequencing efforts continue to uncover more. But how mutations in each of these genes affect brain development remains largely unknown. Although researchers have investigated the molecular effects of just a few genes, testing all of them individually is a daunting task.
In the new work, researchers built on a technique called Perturb-seq, developed in 2016. This technique mutates the genome in individual cells using CRISPR technology and then sequences the RNA in each cell to determine how the mutation changed it.
Perturb-seq has been used in cells grown in a dish, says Paola Arlotta, professor of stem cell and regenerative biology at Harvard University, who co-led the work, “but this is the first time that it is applied in an intact, living and developing organism.”
Arlotta and her colleagues injected viruses carrying CRISPR gene-editing machinery into 12-day-old mouse embryos. They used just enough virus to cause mutations in 1 out of every 1,000 stem cells in the embryonic brain.
When the pups were 7 days old, the researchers sequenced the RNA in five different cell types in the pups’ brains: three types of neurons and two types of glial cells. They then identified groups of mutations in which gene expression had changed in similar ways.
Mutations in several of the autism-linked genes affect common sets of related genes and multiple cell types, they found.
The approach allows researchers to study how different autism-linked genes might converge on similar developmental pathways, says Xin Jin, a junior fellow at Harvard who worked on the study.
The researchers plan to expand the number of genes that the technique can mutate at once, Arlotta says. They also plan to apply it to lab-grown human brain cells that form clusters called organoids, to test whether genes affect development comparably in mice and people.
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