Tubular epithelial organization is a common feature of many developing tissues, including kidneys. Its disruption in pathologies, such as polycystic kidney disease and cancer, highlights the importance of understanding the coordination of all dynamic cellular processes involved in its formation. Polycystic kidney disease is characterized by kidney tubules and lumen disorganization and has long been associated exclusively with dysfunctions of cilia, sensory organelles required for proper cellular functions within tissues. However, recent results, including ours, indicate that intracellular transport complexes involved in kidney cyst formation and initially described for their ciliary roles, also have non-ciliary functions that may contribute to the disease. Our overall objective is to study the non-ciliary roles of these transport complexes, primarily during cell division, in order to identify the cellular mechanisms that contribute to kidney tube morphogenesis in normal and pathological conditions. Our work should lead to an integrated view of the cellular mechanisms involved in kidney tubule morphogenesis and should bring insights into their contributions to pathologies such as kidney cyst formation and cancer.
Centrosomes are microtubule-organizing centers that function at multiple stages of the cell cycle. In non-cycling cells, they contribute to the formation of cilia. In dividing cells, centrosomes are required for mitotic spindle organization and orientation. Centrosome defects have been associated with many diseases, such as ciliopathies, polycystic kidney disease and cancer.
The IntraFlagellar Transport machinery (IFT) in cellular functions and diseases. Cilia proteins of the IFT machinery were initially identified for their link to polycystic kidney disease and their role in cilia. Even if polycystic kidney disease has long been associated exclusively with cilia dysfunctions, recent findings, including our own, suggest that IFT proteins also have non-ciliary roles that could contribute to this pathology. We propose to study the contribution of cell division to the formation of renal tubules in normal and pathological conditions, by focusing on the following questions: (1) What are the non-ciliary roles of IFT proteins? (2) How is cell division organized during kidney tubes morphogenesis? (3) What is the contribution of cell division defects to kidney cyst formation? (4) What is the contribution of IFT proteins to cancer cell division, proliferation and survival?
Proposed approaches to link the cellular scale to the tissue scale. To address questions at the crossroad between cellular biology and diseases, we use cutting edge microscopy techniques on two-dimensional (2D) and three-dimensional (3D) cultures of kidney cells. Indeed, 3D epithelial culture systems, which allow epithelial cells to organize into structures that resemble their in vivo architecture, have emerged as excellent models to study epithelial morphogenesis in a biologically relevant context. To validate and broaden our results, we also take advantage of zebrafish, a powerful in vivo model for visualizing sub-cellular processes during kidney tubule morphogenesis and an attractive vertebrate model to study polycystic kidney disease and cancer.
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IFT proteins spatially control the geometry of cleavage furrow ingression and lumen positioning.
Taulet N, Vitre B, Anguille C, Douanier A, Rocancourt M, Taschner M, Lorentzen E, Echard A, Delaval B.
Nat Commun. 8(1):1928. Pubmed
Flotillins control zebrafish epiboly through their role in cadherin-mediated cell-cell adhesion.
Morris EA, Bodin S, Delaval B, Comunale F, Georget V, Costa ML, Lutfalla G, Gauthier-Rouvière C.
Biol Cell. Pubmed
The use of the NEDD8 inhibitor MLN4924 (Pevonedistat) in a cyclotherapy approach to protect wild-type p53 cells from MLN4924 induced toxicity.
Malhab LJ, Descamps S, Delaval B, Xirodimas DP.
Sci Rep. 6:37775. Pubmed
New frontiers: discovering cilia-independent functions of cilia proteins.
Vertii A, Bright A, Delaval B, Hehnly H, Doxsey S.
EMBO Rep. 16:1275-87. Pubmed
Non-ciliary functions of cilia proteins
Taulet N, Delaval B.
Med Sci (Paris). 30:1040-6. Pubmed
Identification of a mitotic Rac-GEF, Trio, that counteracts MgcRacGAP function during cytokinesis.
Cannet A, Schmidt S, Delaval B, Debant A.
Mol Biol Cell. 25:4063-71. Pubmed
The cilia protein IFT88 is required for spindle orientation in mitosis.
Delaval B, Bright A, Lawson ND, Doxsey S.
Nat Cell Biol. 13(4):461-8. Pubmed
Centrin depletion causes cyst formation and other ciliopathy-related phenotypes in zebrafish.
Delaval B, Covassin L, Lawson ND, Doxsey S.
Cell Cycle. 10(22):3964-72. Pubmed
Pericentrin in cellular function and disease.
Delaval B, Doxsey SJ.
J Cell Biol. 188(2):181-90. Pubmed
Distinct roles of BARD1 isoforms in mitosis: full-length BARD1 mediates Aurora B degradation, cancer-associated BARD1beta scaffolds Aurora B and BRCA2.
Ryser S, Dizin E, Jefford CE, Delaval B, Gagos S, Christodoulidou A, Krause KH, Birnbaum D, Irminger-Finger I.
Cancer Res. 69(3):1125-34. Pubmed
Genetics. Dwarfism, where pericentrin gains stature.
Delaval B, Doxsey S.
Science. 2008 Feb 8;319(5864):732-3. Pubmed