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Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis 总被引:10,自引:0,他引:10
Parviz F Matullo C Garrison WD Savatski L Adamson JW Ning G Kaestner KH Rossi JM Zaret KS Duncan SA 《Nature genetics》2003,34(3):292-296
Although advances have been made in understanding cell differentiation, only rudimentary knowledge exists concerning how differentiated cells form tissues and organs. We studied liver organogenesis because the cell and tissue architecture of this organ is well defined. Approximately 60% of the adult liver consists of hepatocytes that are arranged as single-cell anastomosing plates extending from the portal region of the liver lobule toward the central vein. The basal surface of the hepatocytes is separated from adjacent sinusoidal endothelial cells by the space of Disse, where the exchange of substances between serum and hepatocytes takes place. The hepatocyte's apical surface forms bile canaliculi that transport bile to the hepatic ducts. Proper liver architecture is crucial for hepatic function and is commonly disrupted in disease states, including cirrhosis and hepatitis. Here we report that hepatocyte nuclear factor 4alpha (Hnf4alpha) is essential for morphological and functional differentiation of hepatocytes, accumulation of hepatic glycogen stores and generation of a hepatic epithelium. We show that Hnf4alpha is a dominant regulator of the epithelial phenotype because its ectopic expression in fibroblasts induces a mesenchymal-to-epithelial transition. Most importantly, the morphogenetic parameters controlled by Hnf4alpha in hepatocytes are essential for normal liver architecture, including the organization of the sinusoidal endothelium. 相似文献
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Repping S Skaletsky H Brown L van Daalen SK Korver CM Pyntikova T Kuroda-Kawaguchi T de Vries JW Oates RD Silber S van der Veen F Page DC Rozen S 《Nature genetics》2003,35(3):247-251
Many human Y-chromosomal deletions are thought to severely impair reproductive fitness, which precludes their transmission to the next generation and thus ensures their rarity in the population. Here we report a 1.6-Mb deletion that persists over generations and is sufficiently common to be considered a polymorphism. We hypothesized that this deletion might affect spermatogenesis because it removes almost half of the Y chromosome's AZFc region, a gene-rich segment that is critical for sperm production. An association study established that this deletion, called gr/gr, is a significant risk factor for spermatogenic failure. The gr/gr deletion has far lower penetrance with respect to spermatogenic failure than previously characterized Y-chromosomal deletions; it is often transmitted from father to son. By studying the distribution of gr/gr-deleted chromosomes across the branches of the Y chromosome's genealogical tree, we determined that this deletion arose independently at least 14 times in human history. We suggest that the existence of this deletion as a polymorphism reflects a balance between haploid selection, which culls gr/gr-deleted Y chromosomes from the population, and homologous recombination, which continues to generate new gr/gr deletions. 相似文献
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In this paper we use the abstract syntax and the structural operational semantics of the P systems given in [1], and add probabilities to the rules and to the communication targets. We take into account the number of possible combinations of rules which can be applied in a computation step, as well as the consumption degree of the current resources. 相似文献
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Carla Eller Laura Heydmann Che C. Colpitts Eloi R. Verrier Catherine Schuster Thomas F. Baumert 《Cellular and molecular life sciences : CMLS》2018,75(21):3895-3905
Chronic hepatitis B, C and D virus (HBV, HCV and HDV) infections are a major cause of liver disease and cancer worldwide. Despite employing distinct replication strategies, the three viruses are exclusively hepatotropic, and therefore depend on hepatocyte-specific host factors. The sodium taurocholate co-transporting polypeptide (NTCP), a transmembrane protein highly expressed in human hepatocytes that mediates the transport of bile acids, plays a key role in HBV and HDV entry into hepatocytes. Recently, NTCP has been shown to modulate HCV infection of hepatocytes by regulating innate antiviral immune responses in the liver. Here, we review the current knowledge of the functional role and the molecular and cellular biology of NTCP in the life cycle of the three major hepatotropic viruses, highlight the impact of NTCP as an antiviral target and discuss future avenues of research. 相似文献
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Pujana MA Han JD Starita LM Stevens KN Tewari M Ahn JS Rennert G Moreno V Kirchhoff T Gold B Assmann V Elshamy WM Rual JF Levine D Rozek LS Gelman RS Gunsalus KC Greenberg RA Sobhian B Bertin N Venkatesan K Ayivi-Guedehoussou N Solé X Hernández P Lázaro C Nathanson KL Weber BL Cusick ME Hill DE Offit K Livingston DM Gruber SB Parvin JD Vidal M 《Nature genetics》2007,39(11):1338-1349
Many cancer-associated genes remain to be identified to clarify the underlying molecular mechanisms of cancer susceptibility and progression. Better understanding is also required of how mutations in cancer genes affect their products in the context of complex cellular networks. Here we have used a network modeling strategy to identify genes potentially associated with higher risk of breast cancer. Starting with four known genes encoding tumor suppressors of breast cancer, we combined gene expression profiling with functional genomic and proteomic (or 'omic') data from various species to generate a network containing 118 genes linked by 866 potential functional associations. This network shows higher connectivity than expected by chance, suggesting that its components function in biologically related pathways. One of the components of the network is HMMR, encoding a centrosome subunit, for which we demonstrate previously unknown functional associations with the breast cancer-associated gene BRCA1. Two case-control studies of incident breast cancer indicate that the HMMR locus is associated with higher risk of breast cancer in humans. Our network modeling strategy should be useful for the discovery of additional cancer-associated genes. 相似文献
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Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy 总被引:14,自引:0,他引:14
Pandit B Sarkozy A Pennacchio LA Carta C Oishi K Martinelli S Pogna EA Schackwitz W Ustaszewska A Landstrom A Bos JM Ommen SR Esposito G Lepri F Faul C Mundel P López Siguero JP Tenconi R Selicorni A Rossi C Mazzanti L Torrente I Marino B Digilio MC Zampino G Ackerman MJ Dallapiccola B Tartaglia M Gelb BD 《Nature genetics》2007,39(8):1007-1012
Noonan and LEOPARD syndromes are developmental disorders with overlapping features, including cardiac abnormalities, short stature and facial dysmorphia. Increased RAS signaling owing to PTPN11, SOS1 and KRAS mutations causes approximately 60% of Noonan syndrome cases, and PTPN11 mutations cause 90% of LEOPARD syndrome cases. Here, we report that 18 of 231 individuals with Noonan syndrome without known mutations (corresponding to 3% of all affected individuals) and two of six individuals with LEOPARD syndrome without PTPN11 mutations have missense mutations in RAF1, which encodes a serine-threonine kinase that activates MEK1 and MEK2. Most mutations altered a motif flanking Ser259, a residue critical for autoinhibition of RAF1 through 14-3-3 binding. Of 19 subjects with a RAF1 mutation in two hotspots, 18 (or 95%) showed hypertrophic cardiomyopathy (HCM), compared with the 18% prevalence of HCM among individuals with Noonan syndrome in general. Ectopically expressed RAF1 mutants from the two HCM hotspots had increased kinase activity and enhanced ERK activation, whereas non-HCM-associated mutants were kinase impaired. Our findings further implicate increased RAS signaling in pathological cardiomyocyte hypertrophy. 相似文献