Fischer, E. et al. Defective planar cell polarity in polycystic kidney disease. Nat. Genet. 38, 21-23

Gene Expression and Disease Unit, Centre National de la Recherche Scientifique (CNRS) FRE 2850, Pasteur Institute, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France.
Nature Genetics (Impact Factor: 29.35). 02/2006; 38(1):21-3. DOI: 10.1038/ng1701
Source: PubMed


Morphogenesis involves coordinated proliferation, differentiation and spatial distribution of cells. We show that lengthening of renal tubules is associated with mitotic orientation of cells along the tubule axis, demonstrating intrinsic planar cell polarization, and we demonstrate that mitotic orientations are significantly distorted in rodent polycystic kidney models. These results suggest that oriented cell division dictates the maintenance of constant tubule diameter during tubular lengthening and that defects in this process trigger renal tubular enlargement and cyst formation.

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    • "Oriented cell division appears to be a fundamental mechanism that controls tubular morphogenesis, for example elongation of the mouse nephron in the postnatal period is driven by oriented cell division (Fischer et al., 2006). Remarkably, both the average mitotic angle and the spread of measured angles in the nephron (Fischer et al., 2006) are near identical to the values obtained in this study for beetle tubules. In the nephron, Wnt9B and the planar cell polarity (PCP) pathway control the division plane (Saburi et al., 2008; Karner et al., 2009); these would be further candidates to test in beetle tubules. "
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    ABSTRACT: Malpighian tubules (MpTs) are the major organ for excretion and osmoregulation in most insects. MpT development is characterised for Drosophila melanogaster, but not other species. We therefore do not know the extent to which the MpT developmental programme is conserved across insects. To redress this we provide a comprehensive description of MpT development in the beetle Tribolium castaneum (Coleoptera), a species separated from Drosophila by >315 million years. We identify similarities with Drosophila MpT development including: 1) the onset of morphological development, beginning when tubules bud from the gut and proliferate to increase organ size. 2) the tubule is shaped by convergent-extension movements and oriented cell divisions. 3) differentiated tip cells activate EGF-signalling in distal MpT cells through the ligand Spitz. 4) MpTs contain two main cell types – principal and stellate cells, differing in morphology and gene expression. We also describe development of the beetle cryptonephridial system, an adaptation for water conservation, which represents a major modification of the MpT ground plan characterised by intimate association between MpTs and rectum. This work establishes a new model to compare MpT development across insects, and provides a framework to help understand how an evolutionary novelty – the cryptonephridial system – arose during organ evolution.
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    • "Both cell mitosis and cell migration are polar processes and commonly involve centriole positioning . During mitosis, duplicated centrioles migrate to form an oriented bipolar structure such that cell division occurs specifically either in the plane or perpendicular to the tissue axis, and disruption of mitotic polarity in stratifying epithelia can result in disorders such as polycystic kidney disease, over-proliferation and neoplasia [15] [16] [17]. Centrioles also translocate to the side of the nucleus facing the new leading edge in cells undergoing a change in migratory direction [18] [19]. "
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    ABSTRACT: Establishment of microtubule polarity is critical for directional cell migration involved in morphogenesis, differentiation, cell division, and metastasis. Current models, involving iterative microtubule capture and inactivation of microtubule depolymerizing mechanisms at the leading edge, cannot account for the biased migration exhibited by cells in culture in the absence of directional cues, suggesting central mechanisms governing microtubule polarity remain unknown. We engineered two human MDA-MB-231/IMP1 breast carcinoma cell lines, denoted kdKIF11-1 and kdKIF11-2, in which the kinesin KIF11 (also known as Eg5) was stably knocked down by two different shRNAs. Western blot analysis showed knockdown by each shRNA decreased KIF11 expression by 58 and 79% for kdKIF11-1 and kdKIF11-2, respectively, whereas Rac1 expression was unaffected. All cell lines retained a well-defined microtubule structure. Compared to cells infected with the control viral vector, both KIF11 knockdown cell lines displayed a 14-45% increase in cell motility in a scratch wound healing assay. In contrast, KIF11 knockdown decreased invasion by 70%, compared to the control, as measured by invasion through Matrigel-coated transwells. To determine whether the reduction in invasion was due to reduced chemotaxis, we substituted collagen for Matrigel in the transwell assay and similarly observed a 44%-54% reduction in migration, using EGF as the chemoattractant. However, when including EGF in both the upper and lower chambers of the transwell to stimulate migration but eliminate chemotaxis, transwell migration decreased for the control cell line only, indicating that KIF11 knockdown did not impair migration, but severely impaired chemotaxis. We conclude KIF11 is a key downstream molecule responds to directional cues in chemotaxis to govern the direction of migration.
    Preview · Article · Sep 2014 · Biochemical and Biophysical Research Communications
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    • "Another elegant model proposes that urine flow, acting on the primary cilium, can influence the centrosome localisation and therefore the plane of cell division within the renal tubule. A defect in the cilium would then provoke an inappropriate mechanoresponse with some disoriented cell division and incorrect planar cell polarity, ultimately leading to cystogenesis (Fischer et al. 2006). Kinesin-2 is a heterotrimer formed by KIF3A, KIF3B and KAP3, and is involved in primary cilium growth and the cell cycle (Verhey et al. 2011). "
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    ABSTRACT: Mutations of the two polycystins, PC1 and PC2, lead to polycystic kidney disease. Polycystins are able to form complexes with numerous families of proteins that have been suggested to participate in mechanical sensing. The proposed role of polycystins and their partners in the kidney primary cilium is to sense urine flow. A role for polycystins in mechanosensing has also been shown in other cell types such as vascular smooth muscle cells and cardiac myocytes. At the plasma membrane, polycystins interact with diverse ion channels of the TRP family and with stretch-activated channels (Piezos, TREKs). The actin cytoskeleton and its interacting proteins, such as filaminA, have been shown to be essential for these interactions. Numerous proteins involved in cell-cell and cell-extracellular matrix junctions interact with PC1 and/or PC2. These multimeric protein complexes are important for cell structure integrity, the transmission of force, as well as for mechanosensing and mechanotransduction. A group of polycystin partners are also involved in subcellular trafficking mechanisms. Finally, PC1 and especially PC2 interact with elements of the endoplasmic reticulum and are essential components of calcium homeostasis. In conclusion, we propose that both PC1 and PC2 act as conductors to tune the overall cellular mechanosensitivity.
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