CilMitoPatho · Investigating the role of cilia proteins in dividing cells: implications in kidney cyst formation and ciliopathies

Cilia proteins, including proteins of the intraflagellar transport machinery (IFT) were initially identified for their link to polycystic kidney disease but were also described as potential tumor suppressor. This suggests that common cellular pathways, which have yet to be characterized, might contribute to both benign cyst formation and cancer. Cystogenesis has long been associated exclusively with cilia dysfunction. However, our recent finding of IFT88 functioning in spindle orientation during mitosis suggests that cilia dysfunctions might explain only part of the mechanistic underpinnings of ciliopathies. Indeed, this finding and the fact that several proteins of the IFT machinery localize to spindle poles during mitosis or to the midbody during cytokinesis suggests that cilia proteins, well characterized so far for their role in cilia, might have cilia-independent functions in dividing cells that have yet to be explored.The overall objective of the project is to investigate the roles of cilia proteins in dividing cells and thus to tackle form a different angle the longstanding question of their role in pathologies. First (AIM1), we will identify a list of cilia proteins involved in cell division using High content screening in cultured cells. Then, we will characterize the role of a subset of IFT proteins involved in dividing cells at the cellular (AIM1) and molecular (AIM2) levels. Then (AIM4), we will address in vivo the physiological relevance of mitotic dysfunctions associated with cilia protein depletion in kidney cyst formation using zebrafish.Our general strategy will combine cell biological and biochemical approaches in cultured cells with the use of zebrafish (Danio rerio) to study in vivo cellular processes associated with pathologies. Overall, this project is of great significance since it will unravel novel functions in dividing cells for cilia proteins and will provide new perspectives on the etiology of cyst formation and ciliopathies.