Investigating the role of outer radial glia in autism using human pluripotent stem cells-derived 2D neural cultures and 3D brain organoids
The extraordinary size and folded shape of the human brain makes us the smartest animal on earth. However, it also means many diseases that harm the human brain disrupt cells and structures that are not seen in other animals such as the mouse, and therefore cannot be adequately studied in these animal models. For example, the human brain has a disproportionally large cerebral cortex, compared to mouse and non-human primates. We now know that the evolutionary expansion of the human cortex is driven by a special type of neural stem cells that are abundant in the developing human brain. These neural stem cells are poorly studied because they are very rare in the mouse brain. Autism Spectrum Disorders are complex developmental disorders affecting 1 in 66 children in Canada. Evidence suggests autism has a strong genetic component, and recent efforts have identified a growing list of human genes associated autism. Interestingly, by analyzing the expression levels of these autism genes in different brain cell types, it was revealed that 10% of them are specifically enriched in the special neural stem cells. In the current proposed research, we will directly study the function of these autism genes in human neural stem cells in the dish. To do this, we will grow human stem cells and 3-dimensional brain organoids, and use gene editing tools such as CRISPR to introduce the autism related mutations. We will use these new tools to investigate how autism mutations impact the development and functions of the special neural stem cells in the dish. These elusive stem cells may hold the key to understanding why brain diseases such as autism are so hard to study in animal models. It is only with this understanding can we then develop strategies and medicines to treat these devastating brain diseases.
Yun Li , The Hospital for Sick Children
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