It has recently been shown that embryonic stem (ES) cells grown under appropriate conditions in 3D cultures can give rise to structures termed cerebral organoids that closely resemble embryonic forebrains. This raises the exciting possibility that ES cell-derived cultures could be used to replace mouse embryos in studies of brain development, leading to a significant reduction in the number of animals used in such studies. In this PhD project, the student will (i) establish a robust, reproducible protocol for the derivation of cerebral organoids from mouse ES cells. (ii) Carry out a detailed comparison of the phenotypes of cerebral organoids derived from Pax6, Foxg1 and Gli3 mutant ES cells with those seen in equivalent mouse embryos in vivo, including measurement of cell proliferation rates, differentiation, cell death and expression of key regulatory molecules. (iii) formulate and test one or more specific hypotheses on the mechansim of action of Pax6, Foxg1 or Gli3, using cerebral organoids.
This project has the potential to lead to a reduction of around 75% in 1500-2000 mouse used in our laboratory each year, and we estimate that a potential worldwide reduction of more than 160,000 embryos per year is achievable. Findings from the project will improve our understanding of neurodevelopmental defects and may ultimately contribute to the development of therapeutic approaches.