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31.
32.
Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis 总被引:11,自引:0,他引:11
Hellemans J Preobrazhenska O Willaert A Debeer P Verdonk PC Costa T Janssens K Menten B Van Roy N Vermeulen SJ Savarirayan R Van Hul W Vanhoenacker F Huylebroeck D De Paepe A Naeyaert JM Vandesompele J Speleman F Verschueren K Coucke PJ Mortier GR 《Nature genetics》2004,36(11):1213-1218
Osteopoikilosis, Buschke-Ollendorff syndrome (BOS) and melorheostosis are disorders characterized by increased bone density. The occurrence of one or more of these phenotypes in the same individual or family suggests that these entities might be allelic. We collected data from three families in which affected individuals had osteopoikilosis with or without manifestations of BOS or melorheostosis. A genome-wide linkage analysis in these families, followed by the identification of a microdeletion in an unrelated individual with these diseases, allowed us to map the gene that is mutated in osteopoikilosis. All the affected individuals that we investigated were heterozygous with respect to a loss-of-function mutation in LEMD3 (also called MAN1), which encodes an inner nuclear membrane protein. A somatic mutation in the second allele of LEMD3 could not be identified in fibroblasts from affected skin of an individual with BOS and an individual with melorheostosis. XMAN1, the Xenopus laevis ortholog, antagonizes BMP signaling during embryogenesis. In this study, LEMD3 interacted with BMP and activin-TGFbeta receptor-activated Smads and antagonized both signaling pathways in human cells. 相似文献
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Ding H Wu X Boström H Kim I Wong N Tsoi B O'Rourke M Koh GY Soriano P Betsholtz C Hart TC Marazita ML Field LL Tam PP Nagy A 《Nature genetics》2004,36(10):1111-1116
PDGF-C is a member of the platelet-derived growth factor (PDGF) family, which signals through PDGF receptor (PDGFR) alphaalpha and alphabeta dimers. Here we show that Pdgfc(-/-) mice die in the perinatal period owing to feeding and respiratory difficulties associated with a complete cleft of the secondary palate. This phenotype was less severe than that of Pdgfra(-/-) embryos. Pdgfc(-/-) Pdgfa(-/-) embryos developed a cleft face, subepidermal blistering, deficiency of renal cortex mesenchyme, spina bifida and skeletal and vascular defects. Complete loss of function of both ligands, therefore, phenocopied the loss of PDGFR-alpha function, suggesting that both PDGF-A and PDGF-C signal through PDGFR-alpha to regulate the development of craniofacial structures, the neural tube and mesodermal organs. Our results also show that PDGF-C signaling is a new pathway in palatogenesis, different from, and independent of, those previously implicated. 相似文献
35.
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Mary J. Seller 《Cellular and molecular life sciences : CMLS》1973,29(2):220-221
Résumé Une portion d'une rate allogénique normale été transplantée sur le rein de souris anémiques, génotypeW
v
W
v
, immunosuppressent avec le sérum antilymphocyte; 64% ont guéri. Les cellules hématopoïétiques émigrent hors de la greffe dans la moelle osseuse, s'y fixent, proliférent et remplacent les cellules défectueuses de l'hôte. 相似文献
37.
Lincoln AJ Wickramasinghe D Stein P Schultz RM Palko ME De Miguel MP Tessarollo L Donovan PJ 《Nature genetics》2002,30(4):446-449
In a wide variety of animal species, oocyte maturation is arrested temporarily at prophase of meiosis I (ref. 1). Resumption of meiosis requires activation of cyclin-dependent kinase-1 (CDK1, p34cdc2), one component of maturation-promoting factor (MPF). The dual specificity phosphatases Cdc25a, Cdc25b and Cdc25c are activators of cyclin-dependent kinases; consequently, they are postulated to regulate cell-cycle progression in meiosis and mitosis as well as the DNA-damage response. We generated Cdc25b-deficient (Cdc25b-/-) mice and found that they are viable. As compared with wildtype cells, fibroblasts from Cdc25b-/- mice grew vigorously in culture and arrested normally in response to DNA damage. Female Cdc25b-/- mice were sterile, and Cdc25b-/- oocytes remained arrested at prophase with low MPF activity. Microinjection of wildtype Cdc25b mRNA into Cdc25b-/- oocytes caused activation of MPF and resumption of meiosis. Thus, Cdc25b-/- female mice are sterile because of permanent meiotic arrest resulting from the inability to activate MPF. Cdc25b is therefore essential for meiotic resumption in female mice. Mice lacking Cdc25b provide the first genetic model for studying the mechanisms regulating prophase arrest in vertebrates. 相似文献
38.
Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms 总被引:39,自引:0,他引:39
Barouch LA Harrison RW Skaf MW Rosas GO Cappola TP Kobeissi ZA Hobai IA Lemmon CA Burnett AL O'Rourke B Rodriguez ER Huang PL Lima JA Berkowitz DE Hare JM 《Nature》2002,416(6878):337-339
Subcellular localization of nitric oxide (NO) synthases with effector molecules is an important regulatory mechanism for NO signalling. In the heart, NO inhibits L-type Ca2+ channels but stimulates sarcoplasmic reticulum (SR) Ca2+ release, leading to variable effects on myocardial contractility. Here we show that spatial confinement of specific NO synthase isoforms regulates this process. Endothelial NO synthase (NOS3) localizes to caveolae, where compartmentalization with beta-adrenergic receptors and L-type Ca2+ channels allows NO to inhibit beta-adrenergic-induced inotropy. Neuronal NO synthase (NOS1), however, is targeted to cardiac SR. NO stimulation of SR Ca2+ release via the ryanodine receptor (RyR) in vitro, suggests that NOS1 has an opposite, facilitative effect on contractility. We demonstrate that NOS1-deficient mice have suppressed inotropic response, whereas NOS3-deficient mice have enhanced contractility, owing to corresponding changes in SR Ca2+ release. Both NOS1-/- and NOS3-/- mice develop age-related hypertrophy, although only NOS3-/- mice are hypertensive. NOS1/3-/- double knockout mice have suppressed beta-adrenergic responses and an additive phenotype of marked ventricular remodelling. Thus, NOS1 and NOS3 mediate independent, and in some cases opposite, effects on cardiac structure and function. 相似文献
39.
A gene expression atlas of the central nervous system based on bacterial artificial chromosomes 总被引:1,自引:0,他引:1
Gong S Zheng C Doughty ML Losos K Didkovsky N Schambra UB Nowak NJ Joyner A Leblanc G Hatten ME Heintz N 《Nature》2003,425(6961):917-925
The mammalian central nervous system (CNS) contains a remarkable array of neural cells, each with a complex pattern of connections that together generate perceptions and higher brain functions. Here we describe a large-scale screen to create an atlas of CNS gene expression at the cellular level, and to provide a library of verified bacterial artificial chromosome (BAC) vectors and transgenic mouse lines that offer experimental access to CNS regions, cell classes and pathways. We illustrate the use of this atlas to derive novel insights into gene function in neural cells, and into principal steps of CNS development. The atlas, library of BAC vectors and BAC transgenic mice generated in this screen provide a rich resource that allows a broad array of investigations not previously available to the neuroscience community. 相似文献
40.
The genome sequence of the filamentous fungus Neurospora crassa 总被引:1,自引:0,他引:1
Galagan JE Calvo SE Borkovich KA Selker EU Read ND Jaffe D FitzHugh W Ma LJ Smirnov S Purcell S Rehman B Elkins T Engels R Wang S Nielsen CB Butler J Endrizzi M Qui D Ianakiev P Bell-Pedersen D Nelson MA Werner-Washburne M Selitrennikoff CP Kinsey JA Braun EL Zelter A Schulte U Kothe GO Jedd G Mewes W Staben C Marcotte E Greenberg D Roy A Foley K Naylor J Stange-Thomann N Barrett R Gnerre S Kamal M Kamvysselis M Mauceli E Bielke C Rudd S Frishman D Krystofova S Rasmussen C Metzenberg RL 《Nature》2003,422(6934):859-868
Neurospora crassa is a central organism in the history of twentieth-century genetics, biochemistry and molecular biology. Here, we report a high-quality draft sequence of the N. crassa genome. The approximately 40-megabase genome encodes about 10,000 protein-coding genes--more than twice as many as in the fission yeast Schizosaccharomyces pombe and only about 25% fewer than in the fruitfly Drosophila melanogaster. Analysis of the gene set yields insights into unexpected aspects of Neurospora biology including the identification of genes potentially associated with red light photobiology, genes implicated in secondary metabolism, and important differences in Ca2+ signalling as compared with plants and animals. Neurospora possesses the widest array of genome defence mechanisms known for any eukaryotic organism, including a process unique to fungi called repeat-induced point mutation (RIP). Genome analysis suggests that RIP has had a profound impact on genome evolution, greatly slowing the creation of new genes through genomic duplication and resulting in a genome with an unusually low proportion of closely related genes. 相似文献