Many of the basic principles of biology, and essentially all of the pathways that regulate development, have been identified in what are known as genetics screenings. Originally pioneered in the fruit fly Drosophila and the nematode C. elegans, many genes are inactivated one after the other in genetic studies. By analyzing the consequences of gene loss, scientists can draw conclusions about its function. In this way, for example, all genes that are necessary for the formation of a brain can be identified.
With the help of cerebral organoids, a 3D cell culture model for the human brain that was developed in Jürgen Knoblich’s group at IMBA, CRISPR-LIGHT can now analyze hundreds of mutations for their role in the human brain.
“The basis of the technology is a combination of the well-known CRISPR-Cas9 technology, which was awarded the Nobel Prize in October 2020, and a dual barcoding method. The key trick was to use a guide RNA, but also a genetic barcode, a piece of DNA that we add to the genome of the cells that we use to grow organoids. In this way we can see the entire cell line of each organoid, while with a second barcode we can count the number of cells produced by each start.This reduces noise and so we can see the effect of each guide RNA on the number produced during organoid growth Identify cells. To describe our approach, we have called the method CRIPSR-Lineage Tracing with cellular dissolution in heterogeneous tissue (CRISPR-LIGHT). “, Explains co-first author Dominik Lindenhofer, PhD student at IMBA.
Researchers applied CRISPR-LIGHT to microcephaly, a genetic disorder caused by a decrease in brain size and severe mental impairment in patients. Using this revolutionary new technology, the scientists examined all of the genes that are thought to play a role in the disease.
“With CRISPR-LICHT we could not only identify microcephaly genes, but also identify a specific mechanism for controlling brain size,” says IMBA postdoc and co-first author Christopher Esk. The endoplasmic reticulum (ER) became the main hub in control of extracellular matrix protein secretion. This mechanism affects the integrity of the tissue and therefore the size of the brain and has been identified as a cause of microcephaly.
Genetic studies in Drosophila have long been an established instrument for genome-wide studies and have a long tradition in Vienna. The Vienna Drosophila Research Center (VDRC), which was co-developed by IMBA scientists, is the only Drosophila storage center in Europe and has one of the world’s largest fly collections for functional genetic studies. Jürgen Knoblich, scientific director and group leader of the IMBA, also got his roots in fly genetics and thanks to the fruit fly gained important insights into the role of stem cells in brain development.
“We are very pleased to report that we can now routinely perform genetic testing in complex organoid systems. The method can be applied to other organoid models and to all diseases that affect organ formation. It’s a completely new approach to brain disorder analysis and bears incredible future potential as it can be applied to any brain disease including autism. Our work was only possible because of the collaborative spirit in the Vienna BioCenter, also as groups from our neighboring institutes, the Max Perutz Labs and the Institute for Molecular Pathology, contributed significantly to the ideas that contributed to the development of the new technology, “says Jürgen Knoblich, last author of the study.
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