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Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells 总被引:27,自引:0,他引:27
Nauli SM Alenghat FJ Luo Y Williams E Vassilev P Li X Elia AE Lu W Brown EM Quinn SJ Ingber DE Zhou J 《Nature genetics》2003,33(2):129-137
Several proteins implicated in the pathogenesis of polycystic kidney disease (PKD) localize to cilia. Furthermore, cilia are malformed in mice with PKD with mutations in TgN737Rpw (encoding polaris). It is not known, however, whether ciliary dysfunction occurs or is relevant to cyst formation in PKD. Here, we show that polycystin-1 (PC1) and polycystin-2 (PC2), proteins respectively encoded by Pkd1 and Pkd2, mouse orthologs of genes mutated in human autosomal dominant PKD, co-distribute in the primary cilia of kidney epithelium. Cells isolated from transgenic mice that lack functional PC1 formed cilia but did not increase Ca(2+) influx in response to physiological fluid flow. Blocking antibodies directed against PC2 similarly abolished the flow response in wild-type cells as did inhibitors of the ryanodine receptor, whereas inhibitors of G-proteins, phospholipase C and InsP(3) receptors had no effect. These data suggest that PC1 and PC2 contribute to fluid-flow sensation by the primary cilium in renal epithelium and that they both function in the same mechanotransduction pathway. Loss or dysfunction of PC1 or PC2 may therefore lead to PKD owing to the inability of cells to sense mechanical cues that normally regulate tissue morphogenesis. 相似文献
146.
Lappe-Siefke C Goebbels S Gravel M Nicksch E Lee J Braun PE Griffiths IR Nave KA 《Nature genetics》2003,33(3):366-374
Myelination of axons by oligodendrocytes enables rapid impulse propagation in the central nervous system. But long-term interactions between axons and their myelin sheaths are poorly understood. Here we show that Cnp1, which encodes 2',3'-cyclic nucleotide phosphodiesterase in oligodendrocytes, is essential for axonal survival but not for myelin assembly. In the absence of glial cyclic nucleotide phosphodiesterase, mice developed axonal swellings and neurodegeneration throughout the brain, leading to hydrocephalus and premature death. But, in contrast to previously studied myelin mutants, the ultrastructure, periodicity and physical stability of myelin were not altered in these mice. Genetically, the chief function of glia in supporting axonal integrity can thus be completely uncoupled from its function in maintaining compact myelin. Oligodendrocyte dysfunction, such as that in multiple sclerosis lesions, may suffice to cause secondary axonal loss. 相似文献
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The unique properties of water in the supercooled (metastable) state are not fully understood. In particular, the effects of solutes and mechanical pressure on the kinetics of the liquid-to-solid phase transition of supercooled water and aqueous solutions to ice have remained unresolved. Here we show from experimental data that the homogeneous nucleation of ice from supercooled aqueous solutions is independent of the nature of the solute, but depends only on the water activity of the solution--that is, the ratio between the water vapour pressures of the solution and of pure water under the same conditions. In addition, we show that the presence of solutes and the application of pressure have a very similar effect on ice nucleation. We present a thermodynamic theory for homogeneous ice nucleation, which expresses the nucleation rate coefficient as a function of water activity and pressure. Recent observations from clouds containing ice are in good agreement with our theory and our results should help to overcome one of the main weaknesses of numerical models of the atmosphere, the formulation of cloud processes. 相似文献
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数字地形是指将地球表面的形态以数字的形式进行表达,它通过对地面坐标和高程的数字描述来实现。景观数据的可视化在这里主要指地球表面的一些自然要素,如植被、气候、水等要素在计算机环境下的2维和3维描述。 相似文献
150.
van de Laar IM Oldenburg RA Pals G Roos-Hesselink JW de Graaf BM Verhagen JM Hoedemaekers YM Willemsen R Severijnen LA Venselaar H Vriend G Pattynama PM Collée M Majoor-Krakauer D Poldermans D Frohn-Mulder IM Micha D Timmermans J Hilhorst-Hofstee Y Bierma-Zeinstra SM Willems PJ Kros JM Oei EH Oostra BA Wessels MW Bertoli-Avella AM 《Nature genetics》2011,43(2):121-126
Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-β pathway that is essential for TGF-β signal transmission. SMAD3 mutations lead to increased aortic expression of several key players in the TGF-β pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-β pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis. 相似文献