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10.1242/dev.126.18.4117
125,062,989
Lateral organs produced by shoot apical and flower meristems exhibit a fundamental abaxial-adaxial asymmetry. We describe three members of the YABBY gene family, FILAMENTOUS FLOWER, YABBY2 and YABBY3, isolated on the basis of homology to CRABS CLAW. Each of these genes is expressed in a polar manner in all lateral orga...
10.1038/35067079
An excellent look at several key genes involved in specifying organ polarity in Arabidopsis
10.1126/science.279.5349.399
38,394,749
The possibility that membrane fusion events in the postsynaptic cell may be required for the change in synaptic strength resulting from long-term potentiation (LTP) was examined. Introducing substances into the postsynaptic cell that block membrane fusion at a number of different steps reduced LTP. Introducing SNAP, a ...
10.1038/35072500
Presents evidence that postsynaptic membrane fusion is important for the expression of long-term potentiation.
10.1126/science.287.5461.2262
38,401,141
To elucidate mechanisms that control and execute activity-dependent synaptic plasticity, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPA-Rs) with an electrophysiological tag were expressed in rat hippocampal neurons. Long-term potentiation (LTP) or increased activity of the calcium/calmodulin-dependen...
10.1038/35072500
References 86 and 87 present an elegant series of experiments showing that long-term potentiation involves the CaMKII-dependent delivery of AMPARs to the synaptic plasma membrane.
10.1073/pnas.97.12.6664
1,635,037
The majority of Atm -deficient mice die of malignant thymic lymphoma by 4–5 mo of age. Cytogenetic abnormalities in these tumors are consistently identified within the Tcr α/δ locus, suggesting that tumorigenesis is secondary to aberrant responses to double-stranded DNA breaks that occur during V(D)J recombination. Sin...
10.1038/35056049
References 21 and 22 show that tumorigenesis caused by ATM disruption is delayed when the V(D)J machinery does not make double-stranded breaks in antigen receptor loci. The translocations that can be observed in a RAG-negative background do not involve antigen receptor loci.
10.1101/gad.837100
18,974,825
Ataxia telangiectasia results from mutations of ATM and is characterized by severe neurodegeneration and defective responses to DNA damage. Inactivation of certain DNA repair genes such as DNA ligase IV results in massive neuronal apoptosis and embryonic lethality in the mouse, indicating the occurrence of endogenously...
10.1038/35056049
References 81 – 83 show that the lethality of mutations in genes for DNA ligase IV or Xrcc4 can be relieved by a mutation in the Trp53 or Atm genes. The double-mutant mice develop T-cell tumours at a very young age, showing the involvement of non-homologus end-joining in tumorigenesis.
10.1126/science.279.5349.403
80,828,408
Benign familial neonatal convulsions (BFNC) is an autosomal dominant epilepsy of infancy, with loci mapped to human chromosomes 20q13.3 and 8q24. By positional cloning, a potassium channel gene ( KCNQ2 ) located on 20q13.3 was isolated and found to be expressed in brain. Expression of KCNQ2 in frog ( Xenopus laevis ) o...
10.1038/35036198
Full-length KCNQ2 is cloned and shown to be mutated in affected members of a large family with BFNC. The mutation that truncates the C terminus leads to non-functional channels that have no dominant-negative effect on wild-type subunits.
10.1073/pnas.97.8.4333
81,549,629
Mutations in the potassium channel gene KCNQ4 underlie DFNA2, an autosomal dominant form of progressive hearing loss in humans. In the mouse cochlea, the transcript has been found exclusively in the outer hair cells. By using specific antibodies, we now show that KCNQ4 is situated at the basal membrane of these sensory...
10.1038/35036198
KCNQ4 antibodies are used to show that, in the inner ear, KCNQ4 is expressed primarily in outer hair cells of the cochlea and in type I hair cells of the vestibular organ. Confirming previous speculation that it may mediate potassium efflux, its expression in outer hair cells is restricted to the basal membrane. Surpri...
10.1126/science.7542800
104,228,533
An approach for genome analysis based on sequencing and assembly of unselected pieces of DNA from the whole chromosome has been applied to obtain the complete nucleotide sequence (1,830,137 base pairs) of the genome from the bacterium Haemophilus influenzae Rd. This approach eliminates the need for initial mapping effo...
10.1038/35049551
First sequencing of a free-living organism and first description of use of the shotgun strategy for whole genome sequencing.
10.1046/j.1365-2958.1996.01545.x
102,639,028
The availability of the complete 1.83‐megabase‐pair sequence of the Haemophilus influenzae strain Rd genome has facilitated significant progress in investigating the biology of H. influenzae lipopolysaccharide (LPS), a major virulence determinant of this human pathogen. By searching the H. influenzae genomic database, ...
10.1038/35049551
First example of the exploitation of genome sequence data to investigate the biology of a pathogenic organism.
10.1073/pnas.93.20.11121
103,501,632
The whole genome sequence (1.83 Mbp) of Haemophilus influenzae strain Rd was searched to identify tandem oligonucleotide repeat sequences. Loss or gain of one or more nucleotide repeats through a recombination-independent slippage mechanism is known to mediate phase variation of surface molecules of pathogenic bacteria...
10.1038/35049551
Demonstration of the rapid identification of repeat sequences for the convenient identification of new virulence determinants.
10.1126/science.287.5459.1816
104,238,561
Neisseria meningitidis is a major cause of bacterial septicemia and meningitis . Sequence variation of surface-exposed proteins and cross-reactivity of the serogroup B capsular polysaccharide with human tissues have hampered efforts to develop a successful vaccine. To overcome these obstacles, the entire genome sequenc...
10.1038/35049551
Remarkable demonstration of the use of whole-genome sequence data from an important pathogen Neisseria meningitidis to identify seven conserved surface antigens as vaccine candidates.
10.1126/science.7618105
41,641,356
An insertional mutagenesis system that uses transposons carrying unique DNA sequence tags was developed for the isolation of bacterial virulence genes. The tags from a mixed population of bacterial mutants representing the inoculum and bacteria recovered from infected hosts were detected by amplification, radiolabeling...
10.1038/35049551
First description of signature-tagged mutagenesis which allowed the identification of a second type III secretion system (spiII) in Salmonella typhimurium
10.1530/rep-09-0088
64,275,846
We have recently documented that trisomy 21 mosaicism is common in human foetal ovaries. On the basis of this observation we propose that the maternal age effect in Down syndrome (DS) is caused by the differential behaviour of trisomy 21 in relation to disomy 21 oocytes during development from foetal life until ovulati...
10.1038/35066065
Thoughtful review of possible mechanisms leading to the generation of the maternal-age effect, with a description of a 'limited oocyte pool' hypothesis to explain it.
10.1126/science.289.5477.300
79,485,723
The spindle checkpoint was characterized in meiosis of budding yeast. In the absence of the checkpoint, the frequency of meiosis I missegregation increased with increasing chromosome length, reaching 19% for the longest chromosome. Meiosis I nondisjunction in spindle checkpoint mutants could be prevented by delaying th...
10.1038/35066065
Study demonstrating that in yeast, spindle-checkpoint mutations preferentially affect meiosis I chromosome segregation, and indicating that checkpoint defects might contribute to Down syndrome.
10.1126/science.287.5459.1834
104,040,845
Drosophila exhibits a circadian rest-activity cycle, but it is not known whether fly rest constitutes sleep or is mere inactivity. It is shown here that, like mammalian sleep, rest in Drosophila is characterized by an increased arousal threshold and is homeostatically regulated independently of the circadian clock. As ...
10.1038/35098592
References 5 and 6 indicate that Drosophila show many of the characteristics of the mammalian states of sleep and waking, allowing the fly to be used as a model for the genetic analysis of activity–rest cycles.
10.1126/science.285.5430.1066
122,101,654
The circadian clock consists of a feedback loop in which clock genes are rhythmically expressed, giving rise to cycling levels of RNA and proteins. Four of the five circadian genes identified to date influence responsiveness to freebase cocaine in the fruit fly, Drosophila melanogaster . Sensitization to repeated cocai...
10.1038/35098592
References 15–19 show that many of the same genes are involved in many behavioural phenotypes, such as in learning and sensitivity to ethanol, or circadian rhythms and cocaine response. These findings support the involvement of overlapping pathways and gene networks in behaviour.
10.1073/pnas.94.14.7373
62,049,848
One of the rare examples of a single major gene underlying a naturally occurring behavioral polymorphism is the foraging locus of Drosophila melanogaster . Larvae with the rover allele, for R , have significantly longer foraging path lengths on a yeast paste than do those homozygous for the sitter allele, for s . These...
10.1038/35098592
A good example of experimental evolution in the laboratory, in which larvae with rover or sitter alleles were selected for depending on the degree of crowding.
10.1093/genetics/123.1.157
41,620,470
Abstract Localizing genes for quantitative traits by conventional recombination mapping is a formidable challenge because environmental variation, minor genes, and genetic markers have modifying effects on continuously varying phenotypes. We describe "lethal tagging," a method used in conjunction with deficiency mappin...
10.1038/35098592
This reference reports the genetic localization of the rover–sitter trait by lethal tagging.
10.1126/science.277.5327.834
83,023,487
Naturally occuring polymorphisms in behavior are difficult to map genetically and thus are refractory to molecular characterization. An exception is the foraging gene ( for ), a gene that has two naturally occurring variants in Drosophila melanogaster food-search behavior: rover and sitter. Molecular mapping placed for...
10.1038/35098592
Cloning of the rover–sitter trait; the first example of the molecular identification of a naturally occurring behavioural variation.
10.1126/science.134.3482.835
16,675,743
Previous studies have assumed Drosophila to be negatively geotactic and found this to be the case. New methods of observation now yield a spectrum of geotactic behavior both positive and negative. Two-way selection produces races of animals performing in diametrically opposite fashion to the same stimulus conditions.
10.1038/35098592
One of the first papers to show that a fly behavioural phenotype can be artificially selected for.
10.1073/pnas.68.9.2112
41,569,169
Three mutants have been isolated in which the normal 24-hour rhythm is drastically changed. One mutant is arrhythmic; another has a period of 19 hr; a third has a period of 28 hr. Both the eclosion rhythm of a population and the locomotor activity of individual flies are affected. All these mutations appear to involve ...
10.1038/35098592
This paper reported for the first time a gene (the period gene) that is involved in circadian rhythmicity. This discovery enabled the later genetic and molecular analysis of clock function in many organisms.
10.1093/genetics/154.2.725
20,843,883
Abstract The fruitless (fru) gene functions in Drosophila males to establish the potential for male sexual behaviors. fru encodes a complex set of sex-specific and sex-nonspecific mRNAs through the use of multiple promoters and alternative pre-mRNA processing. The male-specific transcripts produced from the distal (P1)...
10.1038/35098592
Details of the fru splicing pattern were worked out in this paper.
10.1073/pnas.93.18.9687
83,053,786
We have isolated a new Drosophila mutant, satori (sat), the males of which do not court or copulate with female flies. The sat mutation comaps with fruitless (fru) at 91B and does not rescue the bisexual phenotype of fru, indicating that sat is allelic to fru (fru(sat)). The fru(sat) adult males lack a male-specific mu...
10.1038/35098592
References 67 and 68 show that fru , which was known to affect sexual behaviour, acts in the sex-determination pathway.
10.1126/science.8303280
123,149,033
The corpora pedunculata, or mushroom bodies (MBs), in the brain of Drosophila melanogaster adults consist of ∼2500 parallel Kenyon cell fibers derived from four MB neuroblasts. Hydroxyurea fed to newly hatched larvae selectively deletes these cells, resulting in complete, precise MB ablation. Adult flies developing wit...
10.1038/35098592
In this study, the mushroom bodies of flies were chemically ablated to show that these structures have a definitive role in olfactory-based shock-avoidance learning.
10.1126/science.288.5466.672
41,297,708
Memories are thought to be due to lasting synaptic modifications in the brain. The search for memory traces has relied predominantly on determining regions that are necessary for the process. However, a more informative approach is to define the smallest sufficient set of brain structures. The rutabaga adenylyl cyclase...
10.1038/35098592
These authors showed that synaptic plasticity in a small region of the mushroom bodies was sufficient for memory formation. They targeted expression of a rut + transgene in a rut − background to regions of the adult brain.
10.1073/pnas.93.18.9875
81,657,176
Mutations in 12 genes regulating Drosophila melanogaster mushroom body (MB) development were each studied in two genetic backgrounds. In all cases, brain structure was qualitatively or quantitatively different after replacement of the "original" genetic background with that of the Canton Special wild-type strain. The m...
10.1038/35098592
This is the only paper to have systematically tested for genetic background effects on a behaviour, in this case learning.
10.1002/cne.901650405
60,951,851
Abstract We have traced central nervous pathways controlling bird son in the canary using a combination of behavioral and anatomical techniques. Unilateral electrolytic brain lesions were made in adult male canaries whose son had been previously recorded and analysed on a sound spectrograph. After severral days of post...
10.1038/35036205
A combination of lesion, anatomical and behavioural analyses provide the first description of the nuclei essential for vocal control of song, including HVc, RA, Area X and nXII. The authors noted how useful the identification of a discrete system would be for the study of vocal learning, and delineated many of the ques...
10.1126/science.282.5397.2250
16,750,650
Neurons of the song motor control nucleus robustus archistriatalis (RA) exhibited far weaker auditory responses in awake than in anesthetized zebra finches. Remarkably, sleep induced complex patterns of bursts in ongoing activity and uncovered vigorous auditory responses of RA neurons. Local injections of norepinephrin...
10.1038/35036205
Neurons of RA showed far weaker auditory responses in awake than in anaesthetized zebra finches. However, sleep uncovered vigorous auditory responses of RA neurons, and injections of noradrenaline into HVc of anaesthetized birds could mimic the suppression of RA responses normally observed during wakefulness. So audito...
10.1126/science.287.5461.2260
79,485,752
Correct positioning of the mitotic spindle is critical for cell division and development. Spindle positioning involves a search-and-capture mechanism whereby dynamic microtubules find and then interact with specific sites on the submembrane cortex. Genetic, biochemical, and imaging experiments suggest a mechanism for c...
10.1038/35097516
References 61 and 62 provide insights into the search-and-capture mechanism used to align the spindle during mitosis in budding yeast.
10.1113/jphysiol.1995.sp020570
107,220,582
1. Whole‐cell recordings were made from striatal neurones obtained from neonatal rats and maintained in primary cultures. The effects of dopamine D1 receptor activation were studied on the voltage‐gated sodium current. 2. Bath application of a specific D1 agonist, SKF38393 (1 microM), reduced the neuronal excitability ...
10.1038/35077553
Electrophysiological experiments indicating functional modulation of brain sodium channels in striatal neurons by dopamine acting through PKA.
10.1113/jphysiol.1996.sp021604
125,067,318
1. In current‐clamp recordings, 1 microM prostaglandin E2 (PGE2) increased the excitability of neonatal rat dorsal root ganglion neurones. The current threshold for firing was reduced, and the response to a constant suprathreshold stimulation was modified such that a single evoked action potential was converted to a tr...
10.1038/35077553
References 74 – 76 provide compelling evidence for PKA-dependent up-regulation of TTX-resistant sodium channels in sensory neurons.
10.1523/jneurosci.18-01-00488.1998
103,219,923
The nucleus accumbens is a forebrain region that mediates cocaine self-administration and withdrawal effects in animal models of cocaine dependence. Considerable evidence suggests an important role of dopamine D1 receptors in these effects. Using a combination of current-clamp recordings in brain slices and whole-cell ...
10.1038/35077553
Indicates an important role for sodium channel neuromodulation in mediating cocaine effects in the nucleus accumbens.
10.1073/pnas.96.14.7645
65,345,276
Several mechanisms have been identified that may underlie inflammation-induced sensitization of high-threshold primary afferent neurons, including the modulation of voltage- and Ca 2+ -dependent ion channels and ion channels responsible for the production of generator potentials. One such mechanism that has recently re...
10.1038/35077553
Indicates a role for PKA/PKC-dependent upregulation of TTX-resistant sodium current in mediating heightened excitability of nociceptor neurons in response to inflammatory stimuli.
10.1073/pnas.190030497
61,652,984
The protein kinase Chk2, the mammalian homolog of the budding yeast Rad53 and fission yeast Cds1 checkpoint kinases, is phosphorylated and activated in response to DNA damage by ionizing radiation (IR), UV irradiation, and replication blocks by hydroxyurea (HU). Phosphorylation and activation of Chk2 are ataxia telangi...
10.1038/35103059
This study and references 37 and 38 provide evidence for direct phosphorylation of Chk2 by the ATM and ATR kinases in vitro . ATM-dependent phosphorylation of threonine 68 was shown to be required for ionizing-radiation-induced Chk2 activation, also in vivo
10.1126/science.281.5374.272
80,473,774
The Rad53 protein kinase of Saccharomyces cerevisiae is required for checkpoints that prevent cell division in cells with damaged or incompletely replicated DNA. The Rad9 protein was phosphorylated in response to DNA damage, and phosphorylated Rad9 interacted with the COOH-terminal forkhead homology–associated (FHA) do...
10.1038/35103059
The original report that identifies a role for the Rad53 FHA2 domain in phosphospecific interactions between Rad9 and Rad53.
10.1073/pnas.96.24.13777
59,371,127
Stabilization of p53 in response to DNA damage is caused by its dissociation from Mdm2, a protein that targets p53 for degradation in the proteasome. Dissociation of p53 from Mdm2 could be caused by DNA damage-induced p53 posttranslational modifications. The ATM and ATR kinases, whose activation in response to ionizing...
10.1038/35103059
Phosphorylation of the serine 20 residue of p53 was shown to be required for its DNA-damage-dependent stabilization. This was soon followed by identification of Chk1 and Chk2 as the kinases that mediate this phosphorylation (references 53 and 55
10.1126/science.287.5459.1824
26,930,737
Chk2 is a protein kinase that is activated in response to DNA damage and may regulate cell cycle arrest. We generated Chk2-deficient mouse cells by gene targeting. Chk2 −/− embryonic stem cells failed to maintain γ-irradiation–induced arrest in the G 2 phase of the cell cycle. Chk2 −/− thymocytes were resistant to DNA ...
10.1038/35103059
The first ? and, so far, the only ? report on Chk2 -knockout mouse embryo fibroblasts, which indicates an involvement of Chk2 in DNA-damage-dependent stabilization of p53 and G2/M checkpoint arrest.
10.1126/science.288.5470.1425
101,627,180
To protect genome integrity and ensure survival, eukaryotic cells exposed to genotoxic stress cease proliferating to provide time for DNA repair. Human cells responded to ultraviolet light or ionizing radiation by rapid, ubiquitin- and proteasome-dependent protein degradation of Cdc25A, a phosphatase that is required f...
10.1038/35103059
This report and reference 69 shows a rapid, checkpoint-dependent degradation of Cdc25A in response to ultraviolet radiation and stalled replication, respectively.
10.1126/science.286.5449.2528
80,625,022
The hCHK2 gene encodes the human homolog of the yeast Cds1 and Rad53 G 2 checkpoint kinases, whose activation in response to DNA damage prevents cellular entry into mitosis. Here, it is shown that heterozygous germ line mutations in hCHK2 occur in Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usual...
10.1038/35103059
The identification of germline mutations in the CHK2 gene in Li?Fraumeni families with wild-type p53, which indicates a role for CHK2 as a tumour suppressor. Subsequently, identical and additional mutations were found in sporadic cancers of different origin (references 86?88
10.1159/000147530
16,828,765
The organization of embryonic efferent cranial nerves is addressed here by inter-species comparison of segmentally patterned neuromeres, efferent neuronal populations and early mesodermal sources of target muscles. The segmental constancy of these three structural patterns is evaluated for elasmobranch teleost, reptile...
10.1038/35090039
References 6 and 7 describe some phylogenetic differences in hindbrain patterning.
10.1242/dev.127.24.5297
62,613,105
Facial branchiomotor (fbm) neurones undergo a complex migration in the segmented mouse hindbrain. They are born in the basal plate of rhombomere (r) 4, migrate caudally through r5, and then dorsally and radially in r6. To study how migrating cells adapt to their changing environment and control their pathway, we have a...
10.1038/35090039
Here, the role of the basic helix–loop–helix transcription factor in the regulation of transient gene expression patterns and FBM neuron migration is examined, and a functional link between such expression and migratory patterns is suggested.
10.1242/dev.126.8.1621
38,452,099
Hypaxial skeletal muscles develop from migratory and non-migratory precursor cells that are generated by the lateral lip of the dermomyotome. Previous work shows that the formation of migratory precursors requires the c-Met and SF/HGF genes. We show here that in mice lacking c-Met or SF/HGF, the initial development of ...
10.1038/35090039
So far, this signalling system is the only one known to guide one specific cranial nerve towards its target.
10.1073/pnas.96.20.11364
18,934,228
A RING finger-containing protein (AO7) that binds ubiquitin-conjugating enzymes (E2s) and is a substrate for E2-dependent ubiquitination was identified. Mutations of cation-coordinating residues within AO7’s RING finger abolished ubiquitination, as did chelation of zinc. Several otherwise-unrelated RING finger proteins...
10.1038/35056563
This study suggests a general role for RING fingers in ubiquitylation.
10.1073/pnas.190332597
100,358,898
Mutations in the VHL tumor suppressor gene result in constitutive expression of many hypoxia-inducible genes, at least in part because of increases in the cellular level of hypoxia-inducible transcription factor HIF1α, which in normal cells is rapidly ubiquitinated and degraded by the proteasome under normoxic conditio...
10.1038/35056563
References 61?65 establish the VHL?CBC complex as an E3 and show that HIF1α is a substrate.
10.1128/mcb.20.23.8944-8957.2000
28,210,172
ABSTRACT Transcripts harboring premature signals for translation termination are recognized and rapidly degraded by eukaryotic cells through a pathway known as nonsense-mediated mRNA decay (NMD). In addition to protecting cells by preventing the translation of potentially deleterious truncated peptides, studies have su...
10.1038/35067025
Discovery of human and S. pombe homologues of Upf2 allowed the authors to identify regions of the protein with homology to eIF4G. They were able to show interaction of UPF2 with both human eIF4A and human SUI1 by yeast two-hybrid assays.
10.1126/science.278.5336.279
39,403,236
In normal animals, peripheral nerve injury produces a persistent, neuropathic pain state in which pain is exaggerated and can be produced by nonpainful stimuli. Here, mice that lack protein kinase C gamma (PKCγ) displayed normal responses to acute pain stimuli, but they almost completely failed to develop a neuropathic...
10.1038/35053509
References 37 and 38 identify novel targets for treating and understanding the mechanisms that give rise to neuropathic pain.
10.1126/science.286.5444.1558
19,484,628
Substance P receptor (SPR)–expressing spinal neurons were ablated with the selective cytotoxin substance P–saporin. Loss of these neurons resulted in a reduction of thermal hyperalgesia and mechanical allodynia associated with persistent neuropathic and inflammatory pain states. This loss appeared to be permanent. Resp...
10.1038/35053509
References 75 and 76 describe the use of a suicide-ligand approach to selectively target and destroy cells involved in the ascending conduction of pain.
10.1126/science.281.5383.1640
107,396,848
The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induce...
10.1038/35053509
This paper presents both preclinical and clinical data indicating that NK1-receptor antagonists might be useful in the treatment of anxiety and depression.
10.1126/science.277.5328.968
60,159,362
Recent evidence demonstrating multiple regions of human cerebral cortex activated by pain has prompted speculation about their individual contributions to this complex experience. To differentiate cortical areas involved in pain affect, hypnotic suggestions were used to alter selectively the unpleasantness of noxious s...
10.1038/35053509
References 86 and 87 identify the sensory and affective dimensions of pain as being separable and dependent, in part, on different brain circuits.
10.1101/gad.14.8.940
133,917,667
We have investigated the mechanism, structural correlates, and cis -acting elements involved in chromatin opening and gene activation, using the human β-globin locus as a model. Full transcriptional activity of the human β-globin locus requires the locus control region (LCR), composed of a series of nuclease hypersensi...
10.1038/35040083
Indicates that positioning away from the heterochromatin compartment may mediate open chromatin configuration and histone acetylation of the human globin locus.
10.1073/pnas.81.10.3123
122,030,686
Paraformaldehyde-fixed tissue from mouse cerebellum was hybridized with biotin-labeled satellite DNA for identification of centromeres. By using avidin-peroxidase conjugates, it was possible to define the nuclear position of centromeres at the ultrastructural level. Three-dimensional analysis of well-resolved centromer...
10.1038/35040083
One of the first papers showing that the spatial organization of centromeres is non-random and cell-type specific, and indicating that this could represent specific functional capacities.
10.1083/jcb.145.6.1119
20,701,267
Using fluorescence in situ hybridization we show striking differences in nuclear position, chromosome morphology, and interactions with nuclear substructure for human chromosomes 18 and 19. Human chromosome 19 is shown to adopt a more internal position in the nucleus than chromosome 18 and to be more extensively associ...
10.1038/35040083
Analyses the influence of the cell cycle and the inhibition of transcription on the morphology and distribution of specific human chromosome territories.
10.1083/jcb.147.1.13
16,747,950
We have investigated the spatial relationship between transcription sites and chromosome territories in the interphase nucleus of human female fibroblasts. Immunolabeling of nascent RNA was combined with visualization of chromosome territories by fluorescent in situ hybridization (FISH). Transcription sites were found ...
10.1038/35040083
Shows that transcription is compartmentalized, and that sites of active transcription are distinct from sites of inactive chromatin.
10.1242/jcs.113.9.1565
104,368,901
The large-scale chromatin organization of the major histocompatibility complex and other regions of chromosome 6 was studied by three-dimensional image analysis in human cell types with major differences in transcriptional activity. Entire gene clusters were visualized by fluorescence in situ hybridization with multipl...
10.1038/35040083
This paper finds a correlation between the formation of large external chromatin loops, outside a chromosome territory, and the transcriptional activity of a gene cluster.
10.1073/pnas.95.3.1131
58,555,879
Interphasic nuclear organization has a key function in genome biology. We demonstrate that p21 WAF-1 , by influencing gene expression and inducing chromosomal repositioning in tumor suppression, plays a major role as a nuclear organizer. Transfection of U937 tumor cells with p21 WAF-1 resulted in expression of the HUMS...
10.1038/35040083
Global disorganization of nuclear architecture can be associated with cancer, but is reversible during tumour suppression.
10.1126/science.1056602
20,430,573
We report the development of a pseudorabies virus that can be used for retrograde tracing from selected neurons. This virus encodes a green fluorescent protein marker and replicates only in neurons that express the Cre recombinase and in neurons in synaptic contact with the originally infected cells. The virus was inje...
10.1038/35104049
An interesting new technique for neural tracing that combines BAC transgenic mice with genetically altered pseudorabies virus (PRV) expression to allow cell-specific and temporally controlled mapping of neural circuits.
10.1126/science.1065329
83,423,485
The lin-4 and let-7 antisense RNAs are temporal regulators that control the timing of developmental events in Caenorhabditis elegans by inhibiting translation of target mRNAs. let-7 RNA is conserved among bilaterian animals, suggesting that this class of small RNAs [microRNAs (miRNAs)] is evolutionarily ancient. Using ...
10.1038/35103511
The isolation of 15 microRNAs in Caenorhabditis elegans by a combination of cDNA cloning and bioinformatics.
10.1126/science.1065062
125,247,442
Two small temporal RNAs (stRNAs), lin-4 and let-7 , control developmental timing in Caenorhabditis elegans . We find that these two regulatory RNAs are members of a large class of 21- to 24-nucleotide noncoding RNAs, called microRNAs (miRNAs). We report on 55 previously unknown miRNAs in C. elegans . The miRNAs have di...
10.1038/35103511
The isolation of 55 microRNAs in C. elegans by cDNA cloning.
10.1126/science.1064921
41,626,346
In Caenorhabditis elegans , lin-4 and let-7 encode 22- and 21-nucleotide (nt) RNAs, respectively, which function as key regulators of developmental timing. Because the appearance of these short RNAs is regulated during development, they are also referred to as small temporal RNAs (stRNAs). We show that many 21- and 22-...
10.1038/35103511
Describes the isolation of 19 human microRNAs and 14 Drosophila melanogaster microRNAs by cDNA cloning.
10.1101/gad.901001
82,968,823
A burgeoning list of small RNAs with a variety of regulatory functions has been identified in both prokaryotic and eukaryotic cells. However, it remains difficult to identify small RNAs by sequence inspection. We used the high conservation of small RNAs among closely related bacterial species, as well as analysis of tr...
10.1038/35103511
Describes the use of comparative genome analysis and microarray expression studies to predict putative non-coding RNA genes in Escherichia coli , 17 of which were experimentally shown to produce small, non-coding RNA transcripts.
10.1073/pnas.250426397
104,013,517
We have identified three C/D-box small nucleolar RNAs (snoRNAs) and one H/ACA-box snoRNA in mouse and human. In mice, all four snoRNAs (MBII-13, MBII-52, MBII-85, and MBI-36) are exclusively expressed in the brain, unlike all other known snoRNAs. Two of the human RNA orthologues (HBII-52 and HBI-36) share this expressi...
10.1038/35103511
The identification of new small nucleolar RNAs (snoRNAs) that apparently do not modify rRNA, show brain-specific expression and are imprinted genes in the Prader–Willi syndrome region of human, including two different multicopy arrays of snoRNAs HBII-52 and HBII-85
10.1126/science.1062961
125,244,068
The 21-nucleotide small temporal RNA (stRNA) let-7 regulates developmental timing in Caenorhabditis elegans and probably in other bilateral animals. We present in vivo and in vitro evidence that in Drosophila melanogaster a developmentally regulated precursor RNA is cleaved by an RNA interference-like mechanism to prod...
10.1038/35103511
One of the key results that led to the discovery of microRNAs. The enzyme responsible for processing small interfering RNAs is also responsible for processing the endogenous human let-7 regulatory RNA.
10.1101/gad.862301
125,189,789
Double-stranded RNA (dsRNA) induces sequence-specific posttranscriptional gene silencing in many organisms by a process known as RNA interference (RNAi). Using a Drosophila in vitro system, we demonstrate that 21- and 22-nt RNA fragments are the sequence-specific mediators of RNAi. The short interfering RNAs (siRNAs) a...
10.1038/35103511
An excellent biochemical study, showing that double-stranded RNA is processed by an RNase III-like enzyme to make 21–22-nucleotide small interfering RNAs that produce the RNA interference effect.
10.1073/pnas.96.3.1088
16,985,497
Neurons respond to stimuli by integrating generator and synaptic potentials and generating action potentials. However, whether the underlying electrogenic machinery within neurons itself changes, in response to alterations in input, is not known. To determine whether there are changes in Na + channel expression and fun...
10.1038/35090026
Demonstration of plasticity of sodium channel gene expression in the normal adult central nervous system.
10.1073/pnas.95.15.8963
67,544,425
Although physiological and pharmacological evidence suggests the presence of multiple tetrodotoxin-resistant (TTX-R) Na channels in neurons of peripheral nervous system ganglia, only one, SNS/PN3, has been identified in these cells to date. We have identified and sequenced a novel Na channel α-subunit (NaN), predicted ...
10.1038/35090026
References 35–37 report the cloning and sequencing of two sodium channels — Na v 1.8 and Na v 1.9 — that are preferentially expressed in DRG neurons.
10.1152/jn.1994.72.1.466
32,936,185
1. In situ hybridization with subtype-specific probes was used to ask whether there is a change in the types of sodium channels that are expressed in dorsal root ganglion (DRG) neurons after axotomy. 2. Types I and II sodium channel mRNA are expressed at moderate-to-high levels in control DRG neurons of adult rat, but ...
10.1038/35090026
References 38 and 40 report the dysregulation of sodium channel mRNA in peripherally axotomized DRG neurons. Reference 39 demonstrates parallel changes in the sodium channel proteins and currents.
10.1073/pnas.97.21.11598
21,550,346
Clinical abnormalities in multiple sclerosis (MS) have classically been considered to be caused by demyelination and/or axonal degeneration; the possibility of molecular changes in neurons, such as the deployment of abnormal repertoires of ion channels that would alter neuronal electrogenic properties, has not been con...
10.1038/35090026
Demonstration of a channelopathy in an animal model of MS and in human MS.
10.1126/science.289.5481.905
83,320,131
The large ribosomal subunit catalyzes peptide bond formation and binds initiation, termination, and elongation factors. We have determined the crystal structure of the large ribosomal subunit from Haloarcula marismortui at 2.4 angstrom resolution, and it includes 2833 of the subunit's 3045 nucleotides and 27 of its 31 ...
10.1038/35080045
First structure of an archaeal large ribosomal subunit with atomic resolution.
10.1126/science.1060089
107,303,106
We describe the crystal structure of the complete Thermus thermophilus 70 S ribosome containing bound messenger RNA and transfer RNAs (tRNAs) at 5.5 angstrom resolution. All of the 16 S , 23 S , and 5 S ribosomal RNA (rRNA) chains, the A-, P-, and E-site tRNAs, and most of the ribosomal proteins can be fitted to the el...
10.1038/35080045
A near atomic (0.55 nm) resolution map of an entire bacterial ribosome bound by messenger RNAs and transfer RNAs. First detailed view of the intersubunit bridges.
10.1126/science.289.5481.920
20,795,104
Using the atomic structures of the large ribosomal subunit from Haloarcula marismortui and its complexes with two substrate analogs, we establish that the ribosome is a ribozyme and address the catalytic properties of its all-RNA active site. Both substrate analogs are contacted exclusively by conserved ribosomal RNA (...
10.1038/35080045
The peptidyl-transferase centre is described as an RNA cage, with no proteins closer than 1.8 nm to the peptide bond to be synthesized. Peptide-bond formation is proposed to follow the rules of acid–base catalysis as described in serine proteases. The ribosome is described as a ribozyme. Also see references 35 and 36
10.1083/jcb.150.3.447
104,041,758
Three-dimensional cryomaps have been reconstructed for tRNA–ribosome complexes in pre- and posttranslocational states at 17-Å resolution. The positions of tRNAs in the A and P sites in the pretranslocational complexes and in the P and E sites in the posttranslocational complexes have been determined. Of these, the P-si...
10.1038/35080045
Three-dimensional cryo-electron microscopy reconstructions offering snapshot views on the principal positions occupied by transfer RNAs during elongation.
10.1126/science.1060612
107,303,138
Crystal structures of the 30 S ribosomal subunit in complex with messenger RNA and cognate transfer RNA in the A site, both in the presence and absence of the antibiotic paromomycin, have been solved at between 3.1 and 3.3 angstroms resolution. Cognate transfer RNA (tRNA) binding induces global domain movements of the ...
10.1038/35080045
Insights into the decoding process. Demonstration that the geometry of the Watson–Crick base-pair interactions at the codon–anticodon is sensed by specific 16S ribosomal RNA residues upon binding of a cognate tRNA.
10.1126/science.288.5463.107
81,438,739
The crystal structure of a 70-kilodalton ribonucleoprotein complex from the central domain of the Thermus thermophilus 30 S ribosomal subunit was solved at 2.6 angstrom resolution. The complex consists of a 104-nucleotide RNA fragment composed of two three-helix junctions that lie at the end of a central helix, and the...
10.1038/35080045
Insights into the assembly of the small ribosomal subunit. The binding of protein S15 to the central domain of 16S ribosomal RNA is found to induce and stabilize a structural reorganization of the rRNA necessary for binding of subsequent r-proteins.
10.1126/science.280.5366.1086
104,301,889
Familial juvenile polyposis is an autosomal dominant disease characterized by a predisposition to hamartomatous polyps and gastrointestinal cancer. Here it is shown that a subset of juvenile polyposis families carry germ line mutations in the gene SMAD4 (also known as DPC4 ), located on chromosome 18q21.1, that encodes...
10.1038/35094059
Alterations in stromal function predispose colonic epithelial cells to carcinoma.
10.1084/jem.193.6.727
125,085,047
In human breast carcinomas, overexpression of the macrophage colony–stimulating factor (CSF-1) and its receptor (CSF-1R) correlates with poor prognosis. To establish if there is a causal relationship between CSF-1 and breast cancer progression, we crossed a transgenic mouse susceptible to mammary cancer with mice conta...
10.1038/35094059
Showed that macrophages potentiate neoplastic progression through paracrine factors, indicating that these factors are important to tumorigenesis as genetic mutations.
10.1084/jem.190.10.1375
16,746,584
p53 has a key role in the negative regulation of cell proliferation, in the maintenance of genomic stability, and in the suppression of transformation and tumorigenesis. To identify novel regulators of p53, we undertook two functional screens to isolate genes which bypassed either p53-mediated growth arrest or apoptosi...
10.1038/35094059
Macrophage inhibitory factor (MIF) suppress p53-dependent transcriptional activity and blocks senescence of primary mouse embryonic fibroblasts.
10.1073/pnas.73.2.549
18,860,299
A definitive test for developmental totipotency of mouse malignant teratocarcinoma cells was conducted by cloning singly injected cells in genetically marked blastocysts. Totipotency was conclusively shown in an adult mosaic female whose tumor-strain cells had made substantial contributions to all of the wide range of ...
10.1038/35094059
Malignant mouse teratocarcinoma cells, grown through 200 transplant generations over 8 years as in vivo ascites tumours, were microinjected into developing blastocysts. The resulting genetic mosaics were normal, and tumour cells were able to develop into normal tissues.
10.1083/jcb.137.1.231
41,529,726
In a recently developed human breast cancer model, treatment of tumor cells in a 3-dimensional culture with inhibitory β1-integrin antibody or its Fab fragments led to a striking morphological and functional reversion to a normal phenotype. A stimulatory β1-integrin antibody proved to be ineffective. The newly formed r...
10.1038/35094059
Showed that progression to tumorigenicity in a mammary epithelial tumour-progression cell-culture model is accompanied by upregulation of β1-integrins, and that β1-blocking antibodies can restore normal phenotype and suppress tumorigenesis.
10.1126/science.289.5476.113
38,401,929
Loss of cell polarity and tissue architecture are characteristics of malignant cancers derived from epithelial tissues. We provide evidence from Drosophila that a group of membrane-associated proteins act in concert to regulate both epithelial structure and cell proliferation. Scribble (Scrib) is a cell junction–locali...
10.1038/35094059
A genetic screen to identify proteins that mediate epithelial polarity in Drosophila identified a network of two known tumour suppressors and a new gene that are involved in the assembly and maintenance of gap junctions.
10.1242/dev.119.2.419
41,692,921
We have isolated two murine homeobox genes, Nkx-2.5 and Nkx-2.6, that are new members of a sp sub-family of homeobox genes related to Drosophila NK2, NK3 and NK4/msh-2. In this paper, we focus on the Nkx-2.5 gene and its expression pattern during post-implantation development. Nkx-2.5 transcripts are first detected at ...
10.1038/35047564
References 10 and 11 report the isolation of a mouse tinman homologue that is expressed in the developing heart. They represent a turning point for the molecular genetic studies of vertebrate heart formation.
10.1126/science.281.5373.108
62,272,789
Mutations in the gene encoding the homeobox transcription factor NKX2-5 were found to cause nonsyndromic, human congenital heart disease. A dominant disease locus associated with cardiac malformations and atrioventricular conduction abnormalities was mapped to chromosome 5q35, where NKX2-5 , a Drosophila tinman homolog...
10.1038/35047564
This study reports the identification of mutations in human NKX2.5 and their linkage to various forms of congenital heart disease.
10.1242/dev.123.1.285
125,327,746
As part of a large-scale mutagenesis screen of the zebrafish genome, we have identified 58 mutations that affect the formation and function of the cardiovascular system. The cardiovascular system is particularly amenable for screening in the transparent zebrafish embryo because the heart and blood vessels are prominent...
10.1038/35047564
This paper, together with Reference 116 , reports the results of the first large-scale screens for mutations that affect the cardiovascular system in zebrafish.
10.1126/science.282.5396.2072
62,239,816
The trophoblast cell lineage is essential for the survival of the mammalian embryo in utero. This lineage is specified before implantation into the uterus and is restricted to form the fetal portion of the placenta. A culture of mouse blastocysts or early postimplantation trophoblasts in the presence of fibroblast grow...
10.1038/35080570
The derivation of trophoblast stem cells from mouse blastocysts and early postimplantation embryos in the presence of Fgf4 and fibroblast-conditioned medium.
10.1101/gad.873401
81,167,809
The orphan nuclear receptor ERRβ is expressed in undifferentiated trophoblast stem cell lines and extraembryonic ectoderm, and genetic ablation of ERRβ results in abnormal trophoblast proliferation and precocious differentiation toward the giant cell lineage. Here, we show that the synthetic estrogen diethylstilbestrol...
10.1038/35080570
An antagonist of the orphan nuclear hormone receptor, ERRβ, promotes trophoblast-stem-cell differentiation in vivo and in vitro
10.1101/gad.853700a
133,917,750
Placental development is profoundly influenced by oxygen (O 2 ) tension. Human cytotrophoblasts proliferate in vitro under low O 2 conditions but differentiate at higher O 2 levels, mimicking the developmental transition they undergo as they invade the placental bed to establish the maternal–fetal circulation in vivo. ...
10.1038/35080570
Reports the use of trophoblast stem cells and tetraploid aggregation assays to show that Arnt functions to regulate trophoblast cell fate and function, as well as hypoxia responses.
10.1126/science.277.5332.1669
62,007,714
Cytotrophoblasts, specialized placental cells, proliferate early in pregnancy and then differentiate into tumor-like cells that establish blood flow to the placenta by invading the uterus and its vasculature. In this study, cytotrophoblasts cultured under hypoxic conditions (2 percent oxygen), mimicking the environment...
10.1038/35080570
Shows that hypoxia affects human trophoblast development and that it is probably an important regulator of placental function.
10.1073/pnas.90.18.8424
123,032,550
Several newly generated mouse embryonic stem (ES) cell lines were tested for their ability to produce completely ES cell-derived mice at early passage numbers by ES cell <==> tetraploid embryo aggregation. One line, designated R1, produced live offspring which were completely ES cell-derived as judged by isoenzym...
10.1038/35080570
Reported the use of tetraploid-aggregation chimaeras for making embryonic-stem-cell-derived mice.
10.1126/science.8290959
81,428,410
Double-strand DNA breaks (DSBs) occur at recombination hotspots during Saccharomyces cerevisiae meiosis and are thought to initiate exchange at these loci. Analysis of DSB sites in three regions of the yeast genome indicated that breaks occur at or near many potential transcription promoters and that DSBs initiate most...
10.1038/35072078
This analysis showed that double-stranded breaks occur in nuclease-sensitive regions of chromatin.
10.1073/pnas.97.21.11383
103,544,889
In the yeast Saccharomyces cerevisiae , meiotic recombination is initiated by double-strand DNA breaks (DSBs). Meiotic DSBs occur at relatively high frequencies in some genomic regions (hotspots) and relatively low frequencies in others (coldspots). We used DNA microarrays to estimate variation in the level of nearby m...
10.1038/35072078
A microarray-based study that describes mapping of double-stranded breaks throughout the yeast genome.
10.1073/pnas.90.14.6621
27,991,717
The full activity of a recombination initiation site located 5' of HIS4 requires the binding of the transcription factors RAP1, BAS1, and BAS2. Two RAP1 binding sites can substitute for the wild-type initiation site. A 51-bp region of telomeric DNA inserted upstream of either HIS4 or ARG4 very strongly stimulates recom...
10.1038/35072078
This reference describes evidence for α-hot spots — recombination hot spots that require transcription-factor binding.
10.1073/pnas.91.2.609
18,580,218
AP-1 transcriptional activity is stimulated by the transformation promoters phorbol 12-myristate 13-acetate ("12-O-tetradecanoylphorbol 13-acetate," TPA) and epidermal growth factor (EGF) in promotion-sensitive (P+) but not in promotion-resistant (P-) JB6 mouse epidermal cell lines. Although TPA stimulates expression o...
10.1038/35106036
Retinoic acid inhibits TPA-induced transformation and anchorage-independent cell growth in the dose range that blocks TPA-induced AP-1 activity, indicating (as in reference 11 ) that its prevention of tumour promotion might occur through inhibition of AP1 activity.
10.1073/pnas.87.23.9178
19,971,288
Experimental carcinogenesis has led to a concept that defines two discrete stages in the development of skin tumors: (i) initiation, which is accomplished by using a mutagen that presumably activates a protooncogene, and (ii) promotion, which is a reversible process brought about most commonly by repeated application o...
10.1038/35106036
A transgenic mouse strain carrying the activated v- HRAS oncogene developed papillomas, some of which went on to develop squamous-cell carcinomas and, more frequently, sarcomas, following treatment with the tumour promoter TPA. Retinoic acid markedly delayed, reduced and often completely inhibited the appearance of TPA...
10.1182/blood.v100.3.1008
106,728,269
Abstract All-trans retinoic acid (tRA)–induced differentiation in NB4 cells, a cell line derived from an acute promyelocytic leukemia patient with t(15;17) translocation, is markedly facilitated by sodium butyrate (NaB), a histone deacetylase inhibitor (HDACI), or by hexamethylene bisacetamide (HMBA), a non–HDACI tRA-d...
10.1038/35106036
Restoration of retinoic acid-induced differentiation in non-APL AML blasts by co-treatment with an HDAC inhibitor.
10.1073/pnas.96.22.12442
122,097,728
Transforming growth factor β (TGF-β) regulates a variety of physiologic processes, including growth inhibition, differentiation, and induction of apoptosis. Some TGF-β-initiated signals are conveyed through Smad3; TGF-β binding to its receptors induces phosphorylation of Smad3, which then migrates to the nucleus where ...
10.1038/35043051
References 50 and 51 report on the proto-oncogene SKI as a corepressor of SMADs in the basal state.
10.1101/gad.10.19.2462
62,101,673
Metastasis of epithelial tumor cells can be associated with the acquisition of fibroblastoid features and the ability to invade stroma and blood vessels. Using matched in vivo and in vitro culture systems employing fully polarized, mammary epithelial cells, we report here that TGF-beta1 brings about these changes in Ra...
10.1038/35043051
TGF-β is shown to instigate tumorigenic behaviour in transformed mammary cells.
10.1093/genetics/121.1.185
41,774,404
Abstract The advent of complete genetic linkage maps consisting of codominant DNA markers [typically restriction fragment length polymorphisms (RFLPs)] has stimulated interest in the systematic genetic dissection of discrete Mendelian factors underlying quantitative traits in experimental organisms. We describe here a ...
10.1038/35047544
A landmark paper, proposing the use of interval mapping with molecular markers to localize QTL in species that do not contain multiple morphological markers, and developing a maximum likelihood statistical framework to analyse such data.
10.1093/genetics/152.3.1203
41,748,132
Abstract A new statistical method for mapping quantitative trait loci (QTL), called multiple interval mapping (MIM), is presented. It uses multiple marker intervals simultaneously to fit multiple putative QTL directly in the model for mapping QTL. The MIM model is based on Cockerham's model for interpreting genetic par...
10.1038/35047544
References 15 – 17 refine the precision of QTL mapping by including marker cofactors to account for multiple QTL, and extend QTL mapping analysis to include multiple traits and epistasis.
10.1093/genetics/154.1.213
38,206,962
Abstract The nature of genetic variation for Drosophila longevity in a population of recombinant inbred lines was investigated by estimating quantitative genetic parameters and mapping quantitative trait loci (QTL) for adult life span in five environments: standard culture conditions, high and low temperature, and heat...
10.1038/35047544
References 23 and 24 illustrate that QTL effects can depend on the sex, physical environment and genetic environment in which they are estimated.
10.1093/genetics/143.1.293
62,343,123
Abstract Single P-element (P[lArB]) insertional mutagenesis of an isogenic strain was used to identify autosomal loci affecting odor-guided behavior of Drosophila melanogaster. The avoidance response to benzaldehyde of 379 homozygous P[lArB] element-containing insert lines was evaluated quantitatively. Fourteen smell i...
10.1038/35047544
An example of the utility of screening for quantitative effects of insertional mutations to identify new loci that affect quantitative phenotypes.
10.1093/genetics/149.2.999
20,659,053
Abstract A restriction enzyme survey of a 57-kb region including the gene Delta uncovered 53 polymorphic molecular markers in a sample of 55 naturally occurring chromosomes. A permutation test, which assesses the significance of the molecular marker with the largest effect on bristle variation in four genetic backgroun...
10.1038/35047544
An example of the application of linkage disequilibrium mapping at a candidate gene that affects quantitative variation in sensory bristle number, in which limitations of this approach and future directions are discussed.