Dissection of PRC2 function during brain development

How does a brain of correct size and cell composition develop? And what is the role of Polycomb Repressive Complex (PRC)2 in this process? My Elise Richter project aims to tackle this big open question. In my previous Hertha Firnberg project, I was able to show that PRC2 is required in all cells of the developing cortex in order to control correct cortex formation. In my Elise Richter project, I now aim to decipher whether a tissue-wide role of PRC2 can also be observed in other brain regions and may thus be a universal function. To do so, I will color-code individual stem cells in the developing brain of mice and link them to PRC2 mutations. This strategy allows me to understand whether the loss of PRC2 in a single stem cell already affects brain development in different brain regions, or whether altered brain development only occurs when all stem cells in the brain lose PRC2 activity. I will particularly focus on the development of the cerebellum, for which there is currently no data on PRC2 function at all. The cerebellum controls balance, coordination and motor function. Without the cerebellum, we would not be able to properly move at all. Thus, I will also investigate the role of PRC2 in cerebellar development in humans and whether altered activity is present in cerebellar malformations, such as the very rare rhomboencephalosynapsis. To this end, I will access fetal biopsies from the neurobiobank of the Medical University of Vienna and examine them both histologically and using the state-of-the-art sequencing approaches. Using the so-called spatial transcriptomics method, different aspects of cell-cell interactions can be analyzed at the molecular level. This assessment allows me to unravel, which cells of the developing cerebellum show PRC2 activity and how these cells are communicating with each other. The results from the studies will provide a detailed picture of PRC2 function in brain development and may induce a paradigm shift regarding the reciprocal interaction between PRC2 and the cellular environment. The examination of PRC2 in the human brain and a comparison with the results from the mouse studies gives my research a high biological relevance and enables the results to be lifted to a translational level. Thus, my research will contribute to a better characterization and potential treatment of malformations of the developing brain.