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211.
The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression 总被引:8,自引:0,他引:8
Kim JC Badano JL Sibold S Esmail MA Hill J Hoskins BE Leitch CC Venner K Ansley SJ Ross AJ Leroux MR Katsanis N Beales PL 《Nature genetics》2004,36(5):462-470
BBS4 is one of several proteins that cause Bardet-Biedl syndrome (BBS), a multisystemic disorder of genetic and clinical complexity. Here we show that BBS4 localizes to the centriolar satellites of centrosomes and basal bodies of primary cilia, where it functions as an adaptor of the p150(glued) subunit of the dynein transport machinery to recruit PCM1 (pericentriolar material 1 protein) and its associated cargo to the satellites. Silencing of BBS4 induces PCM1 mislocalization and concomitant deanchoring of centrosomal microtubules, arrest in cell division and apoptotic cell death. Expression of two truncated forms of BBS4 that are similar to those found in some individuals with BBS had a similar effect on PCM1 and microtubules. Our findings indicate that defective targeting or anchoring of pericentriolar proteins and microtubule disorganization contribute to the BBS phenotype and provide new insights into possible causes of familial obesity, diabetes and retinal degeneration. 相似文献
212.
Sheen VL Ganesh VS Topcu M Sebire G Bodell A Hill RS Grant PE Shugart YY Imitola J Khoury SJ Guerrini R Walsh CA 《Nature genetics》2004,36(1):69-76
Disruption of human neural precursor proliferation can give rise to a small brain (microcephaly), and failure of neurons to migrate properly can lead to an abnormal arrest of cerebral cortical neurons in proliferative zones near the lateral ventricles (periventricular heterotopia). Here we show that an autosomal recessive condition characterized by microcephaly and periventricular heterotopia maps to chromosome 20 and is caused by mutations in the gene ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2). By northern-blot analysis, we found that mouse Arfgef2 mRNA levels are highest during embryonic periods of ongoing neuronal proliferation and migration, and by in situ hybridization, we found that the mRNA is widely distributed throughout the embryonic central nervous system (CNS). ARFGEF2 encodes the large (>200 kDa) brefeldin A (BFA)-inhibited GEF2 protein (BIG2), which is required for vesicle and membrane trafficking from the trans-Golgi network (TGN). Inhibition of BIG2 by BFA, or by a dominant negative ARFGEF2 cDNA, decreases cell proliferation in vitro, suggesting a cell-autonomous regulation of neural expansion. Inhibition of BIG2 also disturbed the intracellular localization of such molecules as E-cadherin and beta-catenin by preventing their transport from the Golgi apparatus to the cell surface. Our findings show that vesicle trafficking is an important regulator of proliferation and migration during human cerebral cortical development. 相似文献
213.
Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2 总被引:12,自引:0,他引:12
Coste SC Kesterson RA Heldwein KA Stevens SL Heard AD Hollis JH Murray SE Hill JK Pantely GA Hohimer AR Hatton DC Phillips TJ Finn DA Low MJ Rittenberg MB Stenzel P Stenzel-Poore MP 《Nature genetics》2000,24(4):403-409
The actions of corticotropin-releasing hormone (Crh), a mediator of endocrine and behavioural responses to stress, and the related hormone urocortin (Ucn) are coordinated by two receptors, Crhr1 (encoded by Crhr) and Crhr2. These receptors may exhibit distinct functions due to unique tissue distribution and pharmacology. Crhr-null mice have defined central functions for Crhr1 in anxiety and neuroendocrine stress responses. Here we generate Crhr2-/- mice and show that Crhr2 supplies regulatory features to the hypothalamic-pituitary-adrenal axis (HPA) stress response. Although initiation of the stress response appears to be normal, Crhr2-/- mice show early termination of adrenocorticotropic hormone (Acth) release, suggesting that Crhr2 is involved in maintaining HPA drive. Crhr2 also appears to modify the recovery phase of the HPA response, as corticosterone levels remain elevated 90 minutes after stress in Crhr2-/- mice. In addition, stress-coping behaviours associated with dearousal are reduced in Crhr2-/- mice. We also demonstrate that Crhr2 is essential for sustained feeding suppression (hypophagia) induced by Ucn. Feeding is initially suppressed in Crhr2-/- mice following Ucn, but Crhr2-/- mice recover more rapidly and completely than do wild-type mice. In addition to central nervous system effects, we found that, in contrast to wild-type mice, Crhr2-/- mice fail to show the enhanced cardiac performance or reduced blood pressure associated with systemic Ucn, suggesting that Crhr2 mediates these peripheral haemodynamic effects. Moreover, Crhr2-/- mice have elevated basal blood pressure, demonstrating that Crhr2 participates in cardiovascular homeostasis. Our results identify specific responses in the brain and periphery that involve Crhr2. 相似文献
214.
Malaria susceptibility and CD36 mutation 总被引:1,自引:0,他引:1
Aitman TJ Cooper LD Norsworthy PJ Wahid FN Gray JK Curtis BR McKeigue PM Kwiatkowski D Greenwood BM Snow RW Hill AV Scott J 《Nature》2000,405(6790):1015-1016
215.
The RNA-binding protein FCA is an abscisic acid receptor 总被引:2,自引:0,他引:2
The phytohormone abscisic acid (ABA) regulates various physiological processes in plants. The molecular mechanisms by which this is achieved are not fully understood. Genetic approaches have characterized several downstream components of ABA signalling, but a receptor for ABA has remained elusive. Although studies indicate that several ABA response genes encode RNA-binding or RNA-processing proteins, none has been found to be functional in binding ABA. Here we show that FCA, an RNA-binding protein involved in flowering, binds ABA with high affinity in an interaction that is stereospecific and follows receptor kinetics. The interaction between FCA and ABA has molecular effects on downstream events in the autonomous floral pathway and, consequently, on the ability of the plant to undergo transition to flowering. We further show that ABA binding exerts a direct control on the FCA-mediated processing of precursor messenger RNA. Our results indicate that FCA is an ABA receptor involved in RNA metabolism and in controlling flowering time. 相似文献
216.
Beaulieu JP Bennett DP Fouqué P Williams A Dominik M Jørgensen UG Kubas D Cassan A Coutures C Greenhill J Hill K Menzies J Sackett PD Albrow M Brillant S Caldwell JA Calitz JJ Cook KH Corrales E Desort M Dieters S Dominis D Donatowicz J Hoffman M Kane S Marquette JB Martin R Meintjes P Pollard K Sahu K Vinter C Wambsganss J Woller K Horne K Steele I Bramich DM Burgdorf M Snodgrass C Bode M Udalski A Szymański MK Kubiak M Wieckowski T Pietrzyński G Soszyński I Szewczyk O Wyrzykowski L 《Nature》2006,439(7075):437-440
In the favoured core-accretion model of formation of planetary systems, solid planetesimals accumulate to build up planetary cores, which then accrete nebular gas if they are sufficiently massive. Around M-dwarf stars (the most common stars in our Galaxy), this model favours the formation of Earth-mass (M(o)) to Neptune-mass planets with orbital radii of 1 to 10 astronomical units (au), which is consistent with the small number of gas giant planets known to orbit M-dwarf host stars. More than 170 extrasolar planets have been discovered with a wide range of masses and orbital periods, but planets of Neptune's mass or less have not hitherto been detected at separations of more than 0.15 au from normal stars. Here we report the discovery of a 5.5(+5.5)(-2.7) M(o) planetary companion at a separation of 2.6+1.5-0.6 au from a 0.22+0.21-0.11 M(o) M-dwarf star, where M(o) refers to a solar mass. (We propose to name it OGLE-2005-BLG-390Lb, indicating a planetary mass companion to the lens star of the microlensing event.) The mass is lower than that of GJ876d (ref. 5), although the error bars overlap. Our detection suggests that such cool, sub-Neptune-mass planets may be more common than gas giant planets, as predicted by the core accretion theory. 相似文献
217.
218.
Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis 总被引:3,自引:0,他引:3
He C Bassik MC Moresi V Sun K Wei Y Zou Z An Z Loh J Fisher J Sun Q Korsmeyer S Packer M May HI Hill JA Virgin HW Gilpin C Xiao G Bassel-Duby R Scherer PE Levine B 《Nature》2012,481(7382):511-515
Exercise has beneficial effects on human health, including protection against metabolic disorders such as diabetes. However, the cellular mechanisms underlying these effects are incompletely understood. The lysosomal degradation pathway, autophagy, is an intracellular recycling system that functions during basal conditions in organelle and protein quality control. During stress, increased levels of autophagy permit cells to adapt to changing nutritional and energy demands through protein catabolism. Moreover, in animal models, autophagy protects against diseases such as cancer, neurodegenerative disorders, infections, inflammatory diseases, ageing and insulin resistance. Here we show that acute exercise induces autophagy in skeletal and cardiac muscle of fed mice. To investigate the role of exercise-mediated autophagy in vivo, we generated mutant mice that show normal levels of basal autophagy but are deficient in stimulus (exercise- or starvation)-induced autophagy. These mice (termed BCL2 AAA mice) contain knock-in mutations in BCL2 phosphorylation sites (Thr69Ala, Ser70Ala and Ser84Ala) that prevent stimulus-induced disruption of the BCL2-beclin-1 complex and autophagy activation. BCL2 AAA mice show decreased endurance and altered glucose metabolism during acute exercise, as well as impaired chronic exercise-mediated protection against high-fat-diet-induced glucose intolerance. Thus, exercise induces autophagy, BCL2 is a crucial regulator of exercise- (and starvation)-induced autophagy in vivo, and autophagy induction may contribute to the beneficial metabolic effects of exercise. 相似文献
219.
Over a two-year period, Voyager 1 observed a gradual slowing-down of radial plasma flow in the heliosheath to near-zero velocity after April 2010 at a distance of 113.5 astronomical units from the Sun (1 astronomical unit equals 1.5?×?10(8) kilometres). Voyager 1 was then about 20 astronomical units beyond the shock that terminates the free expansion of the solar wind and was immersed in the heated non-thermal plasma region called the heliosheath. The expectation from contemporary simulations was that the heliosheath plasma would be deflected from radial flow to meridional flow (in solar heliospheric coordinates), which at Voyager?1 would lie mainly on the (locally spherical) surface called the heliopause. This surface is supposed to separate the heliosheath plasma, which is of solar origin, from the interstellar plasma, which is of local Galactic origin. In 2011, the Voyager project began occasional temporary re-orientations of the spacecraft (totalling about 10-25 hours every 2 months) to re-align the Low-Energy Charged Particle instrument on board Voyager?1 so that it could measure meridional flow. Here we report that, contrary to expectations, these observations yielded a meridional flow velocity of +3?±?11?km?s(-1), that is, one consistent with zero within statistical uncertainties. 相似文献
220.
Caffau E Bonifacio P François P Sbordone L Monaco L Spite M Spite F Ludwig HG Cayrel R Zaggia S Hammer F Randich S Molaro P Hill V 《Nature》2011,477(7362):67-69
The early Universe had a chemical composition consisting of hydrogen, helium and traces of lithium; almost all other elements were subsequently created in stars and supernovae. The mass fraction of elements more massive than helium, Z, is known as 'metallicity'. A number of very metal-poor stars has been found, some of which have a low iron abundance but are rich in carbon, nitrogen and oxygen. For theoretical reasons and because of an observed absence of stars with Z?1.5?×?10(-5), it has been suggested that low-mass stars cannot form from the primitive interstellar medium until it has been enriched above a critical value of Z, estimated to lie in the range 1.5?×?10(-8) to 1.5?×?10(-6) (ref. 8), although competing theories claiming the contrary do exist. (We use 'low-mass' here to mean a stellar mass of less than 0.8 solar masses, the stars that survive to the present day.) Here we report the chemical composition of a star in the Galactic halo with a very low Z (≤?6.9?×?10(-7), which is 4.5?×?10(-5) times that of the Sun) and a chemical pattern typical of classical extremely metal-poor stars--that is, without enrichment of carbon, nitrogen and oxygen. This shows that low-mass stars can be formed at very low metallicity, that is, below the critical value of Z. Lithium is not detected, suggesting a low-metallicity extension of the previously observed trend in lithium depletion. Such lithium depletion implies that the stellar material must have experienced temperatures above two million kelvin in its history, given that this is necessary to destroy lithium. 相似文献