This project investigates how cell signalling via the primary cilium coordinates the activity of neural stem cells during the development of the cerebral cortex.
The cortex confers humans with their unique cognitive capabilities and relies on a striking diversity of neurons to fulfil its tasks. Generating these different neurons in sufficient numbers requires controlling the balance between proliferation and differentiation of neural stem cells. Changes in these parameters have profound effects on cortical size and underlie cortical malformations in human disease and the evolutionary expansion of the human cerebral cortex.
Coordinating this balance requires communication between cortical stem cells and their environment and involves the primary cilium, a small protrusion from the cell surface that acts as a signalling hub. Defects in the function and/or structure of primary cilia can have severe effects on brain development, however, it remains largely unknown how ciliary defects affect cortical stem cells. To address this question, this project uses mice mutant for Inpp5e which has dual roles in ciliary signalling and stability. Inpp5e inactivation in mice perturbs several signalling pathways important for stem cell function and leads to an enlarged cortex.
This project will investigate how primary cilia mediated signalling determines the balance between stem cell proliferation and neurogenesis. It will employ a combination of in utero electroporation with super resolution and live imaging of primary cilia dynamics in the developing brain. The project will address how Inpp5e controls the assembly and disassembly of the primary cilium and how this is coordinated with the cell cycle of cortical stem cells. It will also investigate whether Inpp5e affects the asymmetric inheritance of cell fate determinants. These analyses will lead to a comprehensive understanding how cilia control stem cell behaviour in the developing cortex and how cortical malformations develop in human diseases caused by defective cilia.
Dr Thomas Theil
Dr Pleasantine Mill