Investigating the roles of cilia proteins in dividing cells: implications in kidney cyst formation and ciliopathies. – CilMitoCyst

Cilia proteins of the intraflagellar transport machinery (IFT) were initially identified in polycystic kidney disease. Cyst formation is characterized by the dilatation and disorganization of tubules. However, the cellular mechanisms that control tissue and tubule morphogenesis remain poorly understood. Cystogenesis has long been associated exclusively with cilia dysfunction but recent results suggest that other pathways may be involved including defects in planar cell polarity. Our finding of IFT88 functioning in spindle orientation during mitosis challenges the current cilia-based model of cytogenesis and suggests that mitotic dysfunctions might contribute to ciliopathy-related phenotypes. It also indicates that cilia proteins might have cilia-independent functions in dividing cells that have yet to be explored. The objective of this research project is to investigate how cilia proteins regulate cellular processes (spindle orientation, cell division) and how they contribute to tissue morphogenesis and pathologies. First (AIM1), we will characterize the role of IFT proteins in dividing cells. Then (AIM2), we will characterize IFT complexes in dividing cells at the molecular level. Finally (AIM3), we will assess the physiological relevance of mitotic dysfunctions associated with cilia potein depletion in pathologies including kidney cyst formation or ciliopathy-related phenotypes. The originality of our approach will be to combine work in cultured cells with the use of zebrafish as an in vivo platform to study cellular processes associated with tissue morphogenesis and pathologies. Overall, this project will unravel novel functions in dividing cells for cilia proteins, will lead to the identification of cilia proteins complexes in mitosis provide which have been well characterized so far only for their role in cilia and will open new perspectives on the role of cilia proteins in pathologies such as polycystic kidney disease or ciliopathy-related phenotypes.