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 highly complex tasks. Generating these different neurons in sufficient numbers requires controlling the balance between proliferation and differentiation of neural stem cells from which these neurons are formed. Changes in these parameters can have profound effects on cortical size and are thought to underlie cortical malformations in human disease and the expansion of the human cerebral cortex during evolution.
Coordinating their proliferation requires communication between cortical stem cells and their environment and involves the primary cilium that acts as a signalling hub in embryonic development and tissue homeostasis. Defects in the function and/or structure of primary cilia can have profound effects on brain development, however, it remains largely unknown how ciliary defects perturb the balance between stem cell division and neurogenesis.
This project will investigate roles of primary cilia in cortical stem cells using mice mutant for the Inpp5e gene which has dual roles in ciliary signalling and in cilia stability. Inpp5e encodes an inositol phosphatase, and its inactivation perturbs several signalling pathways important for stem cell function. Interestingly, Inpp5e mouse mutants present with an elongated, folded cerebral cortex suggesting that Inpp5e coordinates the proliferation and differentiation of cortical stem cells. Indeed, the pool of basal progenitors, an important type of cortical progenitors, is severely depleted in Inpp5e mutants emphasizing Inpp5e’s importance for cortical stem cell development.
The project will test the hypothesis that primary cilia control the signalling required to determine 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. It will address how Inpp5e controls the assembly/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 and how this affects daughter cell fate. These analyses will be a vital step towards gaining a comprehensive understanding of how cilia coordinate the proliferation of cortical stem cells. This research also has implications for our understanding of how cortical malformations develop in ciliopathies, human diseases caused by defects in cilia structure and/or function.
The PhD student will be closely integrated into the Theil and Mill research groups which have overlapping and complementing interests in cortical development and primary cilia. In utero electroporation and high resolution live imaging are well established in the two labs and the candidate will receive extensive training in these cutting-edge methods which are rarely used in this combination. The student will benefit from the excellent research environment and the unique research infrastructure including state of the art animal and super-resolution imaging facilities at the Centre for Discovery Brain Sciences and at the Institute for Genetics and Molecular Medicine.
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Magnani D et al., The ciliogenic transcription factor Rfx3 is required for the formation of the thalamocortical tract by regulating the patterning of prethalamus and ventral telencephalon. Human Molecular Genetics 24, 2578-2593 (2015)
Caparros-Martin JA et al., Specific variants in WDR35 cause a distinctive form of Ellis-van Creveld syndrome by disrupting the recruitment of the EvC complex and SMO into the cilium. Human Molecular Genetics 24, 4126-4137 (2015)