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10.1084/jem.20091756
125,213,845
CD103+ dendritic cells (DCs) in nonlymphoid tissues are specialized in the cross-presentation of cell-associated antigens. However, little is known about the mechanisms that regulate the development of these cells. We show that two populations of CD11c+MHCII+ cells separated on the basis of CD103 and CD11b expression c...
10.1038/nri3149
This study provides an extensive analysis of the transcription factor and cytokine requirements of DCs in non-lymphoid tissues.
10.1126/science.1117729
100,501,637
Macrophages and dendritic cells (DCs) are crucial for immune and inflammatory responses and belong to a network of cells that has been termed the mononuclear phagocyte system (MPS). However, the origin and lineage of these cells remain poorly understood. Here, we describe the isolation and clonal analysis of a mouse bo...
10.1038/nri3149
This study prospectively identified the common progenitor of the monocyte and macrophage lineage and the DC lineage.
10.1126/science.1171243
82,908,628
Rapid Tree Building Phylogenetic reconstruction is used to determine the relationships between organisms and requires an accurate alignment and analysis of multiple sequences. Iterative rounds of alignment and tree building are often necessary to prevent errors in the phylogeny estimate. One such way to address this pr...
10.1038/nri3149
References 21, 40, 61 and 65 together map the developmental steps of DCs from their earliest precursors in the bone marrow to mature cells in the peripheral tissues.
10.1126/science.1164206
62,306,276
Although in vitro observations suggest that cross-presentation of antigens is mediated primarily by CD8α + dendritic cells, in vivo analysis has been hampered by the lack of systems that selectively eliminate this cell lineage. We show that deletion of the transcription factor Batf3 ablated development of CD8α + dendri...
10.1038/nri3149
This study identified BATF3 as an essential regulator of CD8α + DC differentiation and cross-presentation.
10.1038/ncomms10127
124,721,138
Abstract RNA-binding proteins (RBPs) exert a broad range of biological functions. To explore the scope of RBPs across eukaryotic evolution, we determined the in vivo RBP repertoire of the yeast Saccharomyces cerevisiae and identified 678 RBPs from yeast and additionally 729 RBPs from human hepatocytic HuH-7 cells. Comb...
10.1038/nrm.2017.130
RIC was applied in this study to human hepatoma cells (HuH7) and S. cerevisiae . The RNA targets of one of the discovered RBPs, HSD17B10, were identified by iCLIP. This protein binds mitochondrial tRNAs, and a mutation-causing disease abrogates the interaction with RNA.
10.1038/ncomms12128
28,087,706
Abstract The maternal-to-zygotic transition (MZT) is a process that occurs in animal embryos at the earliest developmental stages, during which maternally deposited mRNAs and other molecules are degraded and replaced by products of the zygotic genome. The zygotic genome is not activated immediately upon fertilization, ...
10.1038/nrm.2017.130
This study is the first quantitative RIC analysis to detect differential RBP activity. Here, 116 'dynamic' RBPs were identified during D. melanogaster early embryogenesis.
10.1126/science.aab3369
20,509,629
Orchestrating a viral takeover For some pathogenic viruses, outbreaks occur when a new viral strain emerges and displaces the endemic strain. How such a takeover occurs at a molecular level, however, remains an open question. Manokaran et al. examined one example, the emergence of a new clade of dengue virus (DENV) tha...
10.1038/nrm.2017.130
This work shows that the XRN1-generated, subgenomic RNA of dengue virus interferes with IFNβ induction by sequestering TRIM25, preventing the ubiquitination of RIGI by this protein.
10.1038/ncomms9192
80,459,059
Abstract The flow of genetic information from DNA to protein requires polymerase-II-transcribed RNA characterized by the presence of a 5′-cap. The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its proce...
10.1038/nrm.2017.130
In this study, NCBP3 mediates RNA export through its interaction with NCBP1 following a similar mechanism as NCBP2. NCBP3 is an RBP newly discovered by the RIC studies.
10.1261/rna.052365.115
89,107,763
Mitochondrial RNA processing is an essential step for the synthesis of the components of the electron transport chain in all eukaryotic organisms, yet several aspects of mitochondrial RNA biogenesis and regulation are not sufficiently understood. RNA interactome capture identified several disease-relevant RNA-binding p...
10.1038/nrm.2017.130
This work provides an iCLIP analysis of the noncanonical RBP FASTKD2, showing that FASTKD2 binds mitochondrial RNAs and regulates their metabolism.
10.1083/jcb.200510115
100,796,390
Understanding the mechanisms controlling cancer cell invasion and metastasis constitutes a fundamental step in setting new strategies for diagnosis, prognosis, and therapy of metastatic cancers. LIM kinase1 (LIMK1) is a member of a novel class of serine–threonine protein kinases. Cofilin, a LIMK1 substrate, is essentia...
10.1038/nrc2148
Analysis of the consequences of cofilin pathway activity status on metastasis.
10.1126/science.1192002
62,245,632
A Lot of HOTAIR The roles of several classes of small (<50 nucleotides) noncoding RNAs are beginning to be defined in molecular detail, whereas the function of most of the long (∼200+ nucleotides), intergenic noncoding (linc)RNAs found in most eukaryotic genomes remains something of a mystery. The HOTAIR lincRNA, wh...
10.1038/nrm3679
Illustrates an elegant example of a dominant theme in the lncRNA field whereby lncRNAs physically associate with histone-modifying complexes to regulate chromatin states. Importantly, shows that HOTAIR can also act as a scaffold to organize the concerted actions of two enzymatic activities.
10.1126/science.1228110
107,363,959
Long Noncoding RNAs The past 5 years have uncovered thousands of long (>100 nucleotides) noncoding RNAs (lncRNAs) outpacing our understanding of their functions and mechanisms in regulating the genome. Lee (p. 1435 ) reviews the known and suspected means by which these intriguing molecules control gene expression lo...
10.1038/nrm3679
Provides a particularly compelling example of a mammalian lncRNA, AIRN , which represses target expression by transcriptional interference, as transcriptional overlap of the lncRNA with the target promoter rather than the lncRNA transcript itself is sufficient to interfere with Pol II recruitment.
10.1101/gad.1975011
102,207,349
Transcription of non-protein-coding DNA (ncDNA) and its noncoding RNA (ncRNA) products are beginning to emerge as key regulators of gene expression. We previously identified a regulatory system in Saccharomyces cerevisiae whereby transcription of intergenic ncDNA ( SRG1 ) represses transcription of an adjacent protein-...
10.1038/nrm3679
Demonstrates a novel mode of SER3 gene repression by the yeast lncRNA SRG1 that involves the direction of nucleosome occupancy at the SER3 promoter.
10.1073/pnas.0909641106
109,093,941
The identification of specific functional roles for the numerous long noncoding (nc)RNAs found in eukaryotic transcriptomes is currently a matter of intense study amid speculation that these ncRNAs have key regulatory roles. We have identified a pair of cis -interfering ncRNAs in yeast that contribute to the control of...
10.1038/nrm3679
Provides the first description of the pair of cis -interfering lncRNAs at the FLO11 locus in yeast, where a regulatory circuit toggles between two states of expression depending on the identity of the lncRNA expressed.
10.1126/science.1115901
83,105,946
Noncoding RNA molecules (ncRNAs) have been implicated in numerous biological processes including transcriptional regulation and the modulation of protein function. Yet, in spite of the apparent abundance of ncRNA, little is known about the biological role of the projected thousands of ncRNA genes present in the human g...
10.1038/nrm3679
The first study to functionally screen 512 evolutionarily conserved putative lncRNAs. Identified the NRON lncRNA as a repressor of NFAT nuclear trafficking.
10.1101/gad.455708
60,826,043
Expression of Snail1 in epithelial cells triggers an epithelial–mesenchymal transition (EMT). Here, we demonstrate that the synthesis of Zeb2, a transcriptional repressor of E-cadherin, is up-regulated after Snail1-induced EMT. Snail1 does not affect the synthesis of Zeb2 mRNA, but prevents the processing of a large in...
10.1038/nrm3679
Provides an example of a NAT lncRNA that regulates splicing of the sense encoded mRNA, but with a twist in that the NAT increases protein levels of its target by preventing the splicing of a 5′ UTR IRES-containing intron.
10.1186/1471-2164-14-319
107,362,319
Abstract Background Exosomes, endosome-derived membrane microvesicles, contain specific RNA transcripts that are thought to be involved in cell-cell communication. These RNA transcripts have great potential as disease biomarkers. To characterize exosomal RNA profiles systemically, we performed RNA sequencing analysis u...
10.1038/nrm3679
Characterizes, for the first time, the RNA content of exosomes by RNA sequencing and reveals that lncRNAs are indeed present in these membrane-bound vesicles.
10.1126/science.277.5325.559
67,570,575
Mutations in the gene encoding copper/zinc superoxide dismutase enzyme produce an animal model of familial amyotrophic lateral sclerosis (FALS), a fatal disorder characterized by paralysis. Overexpression of the proto-oncogene bcl-2 delayed onset of motor neuron disease and prolonged survival in transgenic mice express...
10.1038/nrd726
This report provided direct evidence that an apoptosis-blocking protein (BCL2) could prolong survival in an animal model of a chronic neurodegenerative disease, and therefore strengthened the cause-and-effect linkage between the apoptotic machinery and severity or kinetics of neurodegeneration.
10.1126/science.275.5302.983
39,332,100
Heterodimerization between members of the Bcl-2 family of proteins is a key event in the regulation of programmed cell death. The molecular basis for heterodimer formation was investigated by determination of the solution structure of a complex between the survival protein Bcl-x L and the death-promoting region of the ...
10.1038/nrd726
The three-dimensional structure of BCL-X L bound to an inhibitory BH3 peptide laid the foundation for subsequent attempts to screen for, or derive by rational means, small-molecule antagonists of BCL2-family proteins.
10.1073/pnas.97.13.7124
123,036,626
Bcl-2 and related proteins are key regulators of apoptosis or programmed cell death implicated in human disease including cancer. We recently showed that cell-permeable Bcl-2 binding peptides could induce apoptosis of human myeloid leukemia in vitro and suppress its growth in severe combined immunodeficient mice. Here ...
10.1038/nrd726
This paper provided the first evidence that small-molecule inhibitors of BCL2 could be produced.
10.1084/jem.188.1.211
19,701,805
By differential screening of tumor necrosis factor α (TNF-α) and lipopolysaccharide (LPS)- activated endothelial cells (ECs), we have identified a cDNA clone that turned out to be a member of the inhibitor of apoptosis (iap) gene family. iap genes function to protect cells from undergoing apoptotic death in response to...
10.1038/nrd726
This investigation showed a direct link between NF-κB and the expression of IAP-family genes, indicating that the induction of IAP expression represents an important mechanism by which NF-κB prevents TNFα-induced apoptosis in normal cells.
10.1126/science.289.5482.1159
20,263,348
TR3, an immediate-early response gene and an orphan member of the steroid-thyroid hormone-retinoid receptor superfamily of transcription factors, regulates apoptosis through an unknown mechanism. In response to apoptotic stimuli, TR3 translocates from the nucleus to mitochondria to induce cytochrome c release and apopt...
10.1038/nrd726
Showed that steroid/retinoid-family transcription factors can function outside the nucleus to regulate apoptosis, indicating opportunities for the development of small-molecule drugs that modulate this non-nuclear, non-transcriptional activity.
10.1126/science.274.5286.373
17,701,723
The human adenovirus E1B gene encodes a 55-kilodalton protein that inactivates the cellular tumor suppressor protein p53. Here it is shown that a mutant adenovirus that does not express this viral protein can replicate in and lyse p53-deficient human tumor cells but not cells with functional p53. Ectopic expression of ...
10.1038/nrd726
Revealed that a mutant adenovirus only replicates in p53-deficient cells, setting the stage for subsequent clinical trials that were intended to exploit this property for treating cancer patients with p53-deficient tumours.
10.1101/gad.2060811
125,213,538
When directed to the nucleus by TGF-β or BMP signals, Smad proteins undergo cyclin-dependent kinase 8/9 (CDK8/9) and glycogen synthase kinase-3 (GSK3) phosphorylations that mediate the binding of YAP and Pin1 for transcriptional action, and of ubiquitin ligases Smurf1 and Nedd4L for Smad destruction. Here we demonstrat...
10.1038/nrm3434
Shows, together with reference 59, how the nuclear kinases CDK8, CDK9 and GSK3 drive a cycle of SMAD utilization and disposal that is an integral part of canonical BMP and TGFβ pathways.
10.1073/pnas.0906796106
109,100,095
The role of polarity signaling in cancer metastasis is ill defined. Using two three-dimensional culture models of mammary epithelial cells and an orthotopic mouse model of breast cancer, we reveal that Par6 signaling, which is regulated directly by TGFβ, plays a role in breast cancer metastasis. Interference with Par6 ...
10.1038/nrm3434
Shows a non-canonical mode of TGFβ signalling that involves direct phosphorylation of a cell polarity regulator by the TGFβ type II receptor and that facilitates cancer cell invasion.
10.1073/pnas.0605298103
125,306,911
Activation of mammalian innate and acquired immune responses must be tightly regulated by elaborate mechanisms to control their onset and termination. MicroRNAs have been implicated as negative regulators controlling diverse biological processes at the level of posttranscriptional repression. Expression profiling of 20...
10.1038/ni.f.209
This paper identifies three endotoxin-responsive miRNAs (miR-146, miR-155 and miR-132) in monocytic cells and proposes involvement of the miR-146 family in the negative regulation of Toll-like receptor signaling.
10.1126/science.1141229
125,243,857
MicroRNAs are small RNA species involved in biological control at multiple levels. Using genetic deletion and transgenic approaches, we show that the evolutionarily conserved microRNA-155 (miR-155) has an important role in the mammalian immune system, specifically in regulating T helper cell differentiation and the ger...
10.1038/ni.f.209
This report describes analysis of the physiological functions of miR-155 in the immune system through the targeted deletion of this miRNA in mice.
10.1126/science.1139253
19,011,092
MicroRNAs are a class of small RNAs that are increasingly being recognized as important regulators of gene expression. Although hundreds of microRNAs are present in the mammalian genome, genetic studies addressing their physiological roles are at an early stage. We have shown that mice deficient for bic/microRNA-155 ar...
10.1038/ni.f.209
This paper analyzes the physiological functions of miR-155 in the immune system through the targeted deletion of this miRNA in mice.
10.1126/science.1091903
62,305,227
MicroRNAs (miRNAs) are an abundant class of ∼22-nucleotide regulatory RNAs found in plants and animals. Some miRNAs of plants, Caenorhabditis elegans , and Drosophila play important gene-regulatory roles during development by pairing to target mRNAs to specify posttranscriptional repression of these messages. We identi...
10.1038/ni.f.209
This early work demonstrates functions for miRNA in regulating lineage decisions during hematopoiesis, setting the paradigm in this field. It identifies miR-181, miR-142 and miR-223 as being important in hematopoietic development.
10.1128/mcb.19.12.8083
83,421,434
ABSTRACT Many Saccharomyces telomeres bear one or more copies of the repetitive Y′ element followed by ∼350 bp of telomerase-generated C 1–3 A/TG 1–3 repeats. Although most cells lacking a gene required for the telomerase pathway die after 50 to 100 cell divisions, survivors arise spontaneously in such cultures. These ...
10.1038/nrg727
A detailed description of the process of recombination among yeast subtelomeric regions that can maintain telomeric DNA in the absence of telomerase.
10.1093/genetics/136.3.789
125,249,761
Abstract Yeast chromosome ends are composed of several different repeated elements. Among six clones of chromosome ends from two strains of Saccharomyces cerevisiae, at least seven different repeated sequence families were found. These included the previously identified Y' and X elements. Some families are highly varia...
10.1038/nrg727
One of several classic papers by Louis, Haber and colleagues in which they measure recombination frequencies among subtelomeric regions in yeast.
10.1093/genetics/158.3.1111
83,457,400
Abstract Genetically marked P elements inserted into the subtelomeric satellites of Drosophila show repression and variegation of the reporter gene. One such white+ reporter, inserted between the subtelomeric satellite and the terminal HeT-A array in the left arm of chromosome 2 (2L), is sensitive to its context; chang...
10.1038/nrg727
A recent paper showing that the lengthening of the terminal array of HeT-A and TART retrotransposons in Drosophila has an activating influence on a repressed subterminal reporter gene, even from one homologue to the other.
10.1126/science.1062329
103,815,073
In yeast, telomere position effect (TPE) results in the reversible silencing of genes near telomeres. Here we demonstrate the presence of TPE in human cells. HeLa clones containing a luciferase reporter adjacent to a newly formed telomere express 10 times less luciferase than do control clones generated by random integ...
10.1038/nrg727
The first demonstration of telomere position effect in human cells.
10.1242/jcs.00338
60,250,448
To explore mechanisms whereby Malpighian keratinocytes can transdifferentiate into an intestinal-like epithelium, as observed in the early steps of Barrett's esophagus (BE) development, long-standing cultures of esophageal keratinocytes derived from normal mouse esophageal explants were developed. These cells were able...
10.1038/nrc1141
Shows that chronic acid exposure leads to activation of Cdx2 expression in mouse oesophageal keratinocytes.
10.1073/pnas.95.20.11751
41,666,882
Sialic acids are important cell-surface molecules of animals in the deuterostome lineage. Although humans do not express easily detectable amounts of N- glycolylneuraminic acid (Neu5Gc, a hydroxylated form of the common sialic acid N- acetylneuraminic acid, Neu5Ac), it is a major component in great ape tissues, except ...
10.1038/nrg2428
This is the first paper to report that a genetic difference between humans and other hominids results in a definite biochemical change — in human cell-surface sialic acids. Subsequently, more than 10 uniquely human changes in sialic-acid biology have been discovered, as described in reference 89.
10.1101/gr.3737405
107,147,190
The chimpanzee genome sequence is a long-awaited milestone, providing opportunities to explore primate evolution and genetic contributions to human physiology and disease. Humans and chimpanzees shared a common ancestor ∼5-7 million years ago (Mya). The difference between the two genomes is actually not ∼1%, but ∼4%—co...
10.1038/nrg2428
Includes a list of several phenotypic features that show apparent or real differences between humans and great apes.
10.1126/science.1088821
79,691,257
Even though human and chimpanzee gene sequences are nearly 99% identical, sequence comparisons can nevertheless be highly informative in identifying biologically important changes that have occurred since our ancestral lineages diverged. We analyzed alignments of 7645 chimpanzee gene sequences to their human and mouse ...
10.1038/nrg2428
In this key paper, the mouse is used as an outgroup to identify genes undergoing positive selection in humans.
10.1101/gr.2538704
82,228,752
We have analyzed gene expression in various brain regions of humans and chimpanzees. Within both human and chimpanzee individuals, the transcriptomes of the cerebral cortex are very similar to each other and differ more between individuals than among regions within an individual. In contrast, the transcriptomes of the ...
10.1038/nrg2428
This paper was among the first to report comparisons of gene expression in multiple brain regions, including different cerebral cortical areas. The data permit an initial estimation of expression differences between cortical and sub-cortical structures and inter-individual variability.
10.1073/pnas.96.20.11601
58,560,914
In the primary visual area of macaques and other monkeys, layer 4A is a mosaic of separate tissue compartments related to the parvocellular (P) and magnocellular (M) layers of the lateral geniculate nucleus. This mosaic resembles a honeycomb, with thin walls that receive direct P inputs and cores consisting of columns ...
10.1038/nrg2428
Demonstrates fundamental differences in the organization of a primary sensory region between humans and other primates.
10.1126/science.1072047
123,169,169
Primate-specific segmental duplications are considered important in human disease and evolution. The inability to distinguish between allelic and duplication sequence overlap has hampered their characterization as well as assembly and annotation of our genome. We developed a method whereby each public sequence is analy...
10.1038/nrg2428
This is the first validated map of segmental duplication in the human genome. It shows an abundance of interspersed, high-identity duplications and identifies hot spots of disease-associated CNVs.
10.1073/pnas.0605938103
123,910,732
Comparisons of gene expression between human and non-human primate brains have identified hundreds of differentially expressed genes, yet translating these lists into key functional distinctions between species has proved difficult. Here we provide a more integrated view of human brain evolution by examining the large-...
10.1038/nrg2428
The first demonstration that network-based approaches permit a functional assessment of changes in gene expression in an evolutionary context.
10.1073/pnas.96.9.5268
60,726,611
We report the existence and distribution of an unusual type of projection neuron, a large, spindle-shaped cell, in layer Vb of the anterior cingulate cortex of pongids and hominids. These spindle cells were not observed in any other primate species or any other mammalian taxa, and their volume was correlated with brain...
10.1038/nrg2428
Demonstrates that a neuronal type, although not specific to humans, is likely to be an important feature of human brain evolution. This paper is a critical proof of principle study that, similar to reference 61, highlights the importance of phenotype discovery.
10.7551/mitpress/2871.001.0001
79,688,296
The role of genetic inheritance dominates current evolutionary theory. At the end of the nineteenth century, however, several evolutionary theorists independently speculated that learned behaviors could also affect the direction and rate of evolutionary change. This notion was called the Baldwin effect, after the psych...
10.1038/nrg2428
A compendium of interesting articles discussing many aspects of the definitions and implications of the Baldwin effect.
10.1073/pnas.93.8.3444
62,552,383
The CBFA2 (AML1) gene encodes a DNA-binding subunit of the heterodimeric core-binding factor. The CBFA2 gene is disrupted by the (8;21), (3;21), and (12;21) chromosomal translocations associated with leukemias and myelodysplasias in humans. Mice lacking a CBF alpha 2 protein capable of binding DNA die between embryonic...
10.1038/nrc840
These two reports characterize the phenotype of Runx1 -knockout mice, and show an absolute requirement for Runx1 for definitive haematopoiesis.
10.1242/dev.126.11.2563
104,420,699
Cbfa2 (AML1) encodes the DNA-binding subunit of a transcription factor in the small family of core-binding factors (CBFs). Cbfa2 is required for the differentiation of all definitive hematopoietic cells, but not for primitive erythropoiesis. Here we show that Cbfa2 is expressed in definitive hematopoietic progenitor ce...
10.1038/nrc840
This study shows the requirement for Runx1 for the development of haematopoietic clusters in several main arteries during development.
10.4049/jimmunol.178.7.4230
78,920,905
Abstract Mouse small intestine intraepithelial lymphocytes (IEL) that express αβTCR and CD8αα homodimers are an enigmatic T cell subset, as their specificity and in vivo function remain to be defined. To gain insight into the nature of these cells, we performed global gene expression profiling using microarray analysis...
10.1038/nri3007
References 17 and 18 suggest that CD8αα + TCRαβ + IEL precursor cells acquire functional specialization during their differentiation in the thymus. Their unique functional and phenotypic differentiation is reflected in the gene signature that they display at the mature stage as CD8αα + TCRαβ + IELs.
10.1126/science.1063564
106,964,386
The thymus leukemia antigen (TL) is a nonclassical class I molecule, expressed abundantly on intestinal epithelial cells. We show that, in contrast to other major histocompatibility complex (MHC) class I molecules that bind CD8αβ, TL preferentially binds the homotypic form of CD8α (CD8αα). Thus, TL tetramers react spec...
10.1038/nri3007
Identified TLA as a high-affinity ligand for CD8αα and showed functional effects of the interaction between TLA and CD8αα homodimers.
10.1084/jem.180.4.1345
26,352,049
The epithelium of the small intestine in normal euthymic mice contains a large number of intraepithelial lymphocytes (IEL), some of which bear a T cell receptor alpha/beta (TCR-alpha/beta). About half of these TCR-alpha/beta IEL display the CD8 alpha alpha phenotype and the remaining have the CD8 alpha beta or the CD4 ...
10.1038/nri3007
This study describes the oligoclonal repertoire of TCRαβ + IELs in mice.
10.1002/eji.1830200814
81,007,961
Abstract Neonatal treatment of BALB/c mice with anti‐V H T15 antibodies suppresses serum expression of V H T15 immunoglobulins in adult animals (2 months) which remains for over 8 months in half of the cases. Suppressed mice, however, contain control numbers of B cells expressing genes of the S107 V H family and produc...
10.1038/nri3007
References 59 and 62 describe the relevance of microbial colonization for the development of different IEL populations.
10.1084/jem.20011793
122,097,998
Lymphocytes residing in the intestinal epithelium are exclusively T cells and account for one of the largest collection of T cells in the organism. However, their function remains obscure. We and others have shown that the development of intestinal intraepithelial T cells is compromised in mutant mice prone to chronic ...
10.1038/nri3007
Details a protective role for CD8αα + TCRαβ + IELs in preventing inflammation induced by conventional CD4 + T cells in a model of induced colitis.
10.1126/science.7973709
104,301,637
The role played in immune surveillance by γδ T cells residing in various epithelia has not been clear. It is shown here that activated γδ T cells obtained from skin and intestine express the epithelial cell mitogen keratinocyte growth factor (KGF). In contrast, intraepithelial αβ T cells, as well as all lymphoid αβ and...
10.1038/nri3007
References 90–92 describe protective roles for TCRγδ + IELs in intestinal epithelial cell growth and turnover and epithelium homeostasis.
10.4049/jimmunol.161.9.4902
139,040,091
Abstract Intraepithelial lymphocytes (IEL) of the intestine represent an important barrier in the prevention of infection against orally acquired pathogens. Adoptive transfer of Ag-primed IEL into a naive host can protect against challenge. Using a murine model, we demonstrate in two genetically distinct mouse strains ...
10.1038/nri3007
Describes a role for IFNγ-producing TCRαβ + CD8αα + IELs in the protection against an intestinal infection with parasites.
10.1073/pnas.86.14.5527
28,128,837
The intraepithelial cells of the murine small intestine include a significant number of CD3+ T cells that use T-cell receptor gamma genes rather than T-cell receptor beta genes. As with other sites of T-cell receptor gamma expression, combinatorial diversity is limited, but there is junctional diversity, and this, toge...
10.1038/nri3007
Together with reference 103, references 106 and 107describe the restricted repertoire of TCRγδ + IELs.
10.1126/science.1058867
61,471,021
Many intracellular pathogens infect a broad range of host tissues, but the importance of T cells for immunity in these sites is unclear because most of our understanding of antimicrobial T cell responses comes from analyses of lymphoid tissue. Here, we show that in response to viral or bacterial infection, antigen-spec...
10.1038/nri3007
Details preferential effector memory cell differentiation and cytotoxic function of intestinal CD8 + TCRαβ + IELs in response to infections.
10.1182/blood-2002-02-0569
18,755,861
Abstract The c-fms gene encodes the receptor for macrophage colony-stimulating factor (CSF-1). The gene is expressed selectively in the macrophage and trophoblast cell lineages. Previous studies have indicated that sequences in intron 2 control transcript elongation in tissue-specific and regulated expression of c-fms....
10.1038/nri2528
This study uses a valuable reporter mouse strain for studying the mononuclear phagocytic system in development and disease.
10.1242/dev.120.6.1357
83,543,023
Colony stimulating factor-1 (CSF-1) regulates the survival, proliferation and differentiation of mononuclear phagocytes. The osteopetrotic (op/op) mutant mouse is devoid of CSF-1 due to an inactivating mutation in the CSF-1 gene and is deficient in several mononuclear phagocyte subpopulations. To analyze more fully the...
10.1038/nri2528
This paper provides a detailed characterization of macrophage deficiencies in Csf1 op/op mice.
10.1126/science.8171324
62,295,476
The in vivo function of murine granulocyte-macrophage colony-stimulating factor (GM-CSF) was investigated in mice, carrying a null allele of the GM-CSF gene, that were generated by gene targeting techniques in embryonic stem cells. Although steady-state hematopoiesis was unimpaired in homozygous mutant animals, all ani...
10.1038/nri2528
In this study and in reference 25, the generation of a mouse lacking GM-CSF indicates that this growth factor does not have a role in the regulation of the myeloid lineage in normal physiological conditions.
10.1073/pnas.87.12.4828
103,381,252
Osteopetrotic (op/op) mutant mice suffer from congenital osteopetrosis due to a severe deficiency of osteoclasts. Furthermore, the total number of mononuclear phagocytes is extremely low in affected mice. Serum, 11 tissues, and different cell and organ conditioned media from op/op mice were shown to be devoid of biolog...
10.1038/nri2528
This is the original characterization of mice lacking CSF1 because of an inactivating mutation in the Csf1 gene.
10.1073/pnas.91.20.9312
107,205,196
The study of colony stimulating factor 1 (CSF-1), a homodimeric serum growth factor that regulates mononuclear phagocytes and is involved in maternal-fetal interactions during pregnancy, was dramatically enhanced by the observation that the recessive mutation osteopetrosis, op, is an inactivating mutation in the CSF-1-...
10.1038/nri2528
References 45 and 47 show that macrophages regulate branching morphogenesis in the mammary gland.
10.1210/mend.11.11.0009
59,141,437
Abstract Colony-stimulating factor-1 (CSF-1) is the principal regulator of cells of the mononuclear phagocytic lineage that includes monocytes, tissue macrophages, microglia, and osteoclasts. Macrophages are found throughout the reproductive tract of both males and females and have been proposed to act as regulators of...
10.1038/nri2528
This study shows that CSF1-regulated microglial cells help to establish the hypothalamic–pituitary–gonadal axis during development.
10.1242/dev.122.9.2661
62,619,412
Colony stimulating factor-1 (CSF-1) was initially identified as a growth factor for mononuclear phagocytes. This study examines the role of CSF-1 in the development of the central nervous system (CNS). CSF-1 treatment of neurons cultured from embryonic brain promoted survival and process outgrowth in a dose-dependent m...
10.1038/nri2528
The first study to indicate that the lack of CSF1 signalling in microglial cells perturbs brain physiology.
10.1242/dev.012187
16,710,185
Macrophages have a critical function in the recognition and engulfment of dead cells. In some settings, macrophages also actively signal programmed cell death. Here we show that during developmentally scheduled vascular regression,resident macrophages are an obligatory participant in a signaling switch that favors deat...
10.1038/nri2528
References 69 and 70 show that macrophages are essential for vascular patterning in the eye.
10.1126/science.292.5521.1546
102,461,028
Mature erythrocytes in mammals have no nuclei, although they differentiate from nucleated precursor cells. The mechanism by which enucleation occurs is not well understood. Here we show that deoxyribonuclease II (DNase II) is indispensable for definitive erythropoiesis in mouse fetal liver. No live DNase II–null mice w...
10.1038/nri2528
This study identifies a new function for macrophages in erythropoiesis.
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/nri2528
This paper shows that macrophages have an important role in promoting tumour progression and metastasis.
10.1126/science.1120800
62,159,235
Microbial resistance to antibiotics currently spans all known classes of natural and synthetic compounds. It has not only hindered our treatment of infections but also dramatically reshaped drug discovery, yet its origins have not been systematically studied. Soil-dwelling bacteria produce and encounter a myriad of ant...
10.1038/nrmicro1614
This manuscript describes a systematic study of the level of antibiotic resistance in a population of environmental bacteria that demonstrates that multidrug resistance is much more prevalent than previously thought.
10.1073/pnas.70.8.2276
122,681,240
Various species of Streptomyces possess aminoglycoside-modifying enzymes. Streptomyces kanamyceticus contains an enzyme that acetylates the 6′-amino group of kanamycin A and B, gentamicin C 1a , and neomycin. Streptomyces spectabilis produces an enzyme that acetylates the 2′-amino group of the hexose ring of gentamicin...
10.1038/nrmicro1614
First study to show the similarity of antibiotic resistance mechanisms in pathogenic bacteria and antibiotic producers.
10.1111/j.1462-2920.2004.00664.x
82,376,159
Summary Antibiotic resistance genes are typically isolated by cloning from cultured bacteria or by polymerase chain reaction (PCR) amplification from environmental samples. These methods do not access the potential reservoir of undiscovered antibiotic resistance genes harboured by soil bacteria because most soil bacter...
10.1038/nrmicro1614
First report of antibiotic resistance genes in the soil bacterial metagenome.
10.1126/science.1080944
123,204,080
Cell polarization can occur in the absence of any spatial cues. To investigate the mechanism of spontaneous cell polarization, we used an assay in yeast where expression of an activated form of Cdc42, a Rho-type guanosine triphosphatase (GTPase) required for cell polarization, could generate cell polarity without any r...
10.1038/nrm2522
Shows a simple mechanism in yeast for symmetry breaking that involves a positive-feedback loop composed of actin- and myosin-mediated transport of the signalling molecule Cdc42, and Cdc42-controlled assembly of orientated actin arrays.
10.1083/jcb.200707042
83,052,052
Axon formation is the initial step in establishing neuronal polarity. We examine here the role of microtubule dynamics in neuronal polarization using hippocampal neurons in culture. We see increased microtubule stability along the shaft in a single neurite before axon formation and in the axon of morphologically polari...
10.1038/nrm2522
Shows that microtubule stabilization in one of the minor neurites of hippocampal neurons is sufficient to break symmetry and specify the formation of an axon.
10.1083/jcb.200302175
103,777,288
Post-Golgi carriers of various newly synthesized axonal membrane proteins, which possess kinesin (KIF5)-driven highly processive motility, were transported from the TGN directly to axons. We found that KIF5 has a preference to the microtubules in the initial segment of axon. Low dose paclitaxel treatment caused missort...
10.1038/nrm2522
References 97 and 98 provide evidence that the kinesin motor domain alone is capable of interpreting cues from microtubules to direct their translocation into specific neuronal processes.
10.1083/jcb.200709029
62,297,383
A critical microtubule (MT) polarization event in cell migration is the Rho/mDia-dependent stabilization of a subset of MTs oriented toward the direction of migration. Although mDia nucleates actin filaments, it is unclear whether this or a separate activity of mDia underlies MT stabilization. We generated two actin mu...
10.1038/nrm2522
Shows that a formin, mDia2, with known actin-nucleation activity, independently and directly stabilizes microtubules.
10.1073/pnas.1004060107
104,164,897
Defects in apical-basal cell polarity and abnormal expression of cell polarity determinants are often associated with cancer in vertebrates. In Drosophila , abnormal expression of apical-basal determinants can cause neoplastic phenotypes, including loss of cell polarity and overproliferation. However, the pathways thro...
10.1038/nrc3169
References 74, 75, 84 and 85 provide evidence that the cell polarity regulators LGL, aPKC and CRB regulate proliferation and survival in the developing eye and imaginal disc epithelia by controlling activity of the Hippo tumour suppressor pathway in D. melanogaster
10.1073/pnas.0911427107
38,447,934
How organ size is controlled in mammals is not currently understood. In Drosophila the Hippo signaling pathway functions to suppress growth in imaginal discs and has been suggested to control organ size. To investigate the role of hippo signaling in regulation of mammalian organ size we have generated conditional allel...
10.1038/nrc3169
References 39, 95, 96 and 97 link merlin to mammalian Hippo signalling and implicate YAP1 activation as a mediator of phenotypes that occur in patients with neurofibromatosis type II.
10.1073/pnas.0610157104
104,400,331
AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that plays an important role in maintaining cellular energy balance. The activity of AMPK is modulated both by the cellular AMP-to-ATP ratio and by upstream kinases. Recently, AMPK was shown to be phosphorylated and activated by LKB1, a protein ki...
10.1038/nrc3169
References 110–113 provide substantial evidence that LKB1, through AMPK activation and not PAR1 activation, controls cell polarity in D. melanogaster and tight junction formation in human cells. The role of LKB1 and AMPK in cell polarity is mediated by the reorganization of the actin cytoskeleton through the motor prot...
10.1083/jcb.200910021
109,032,022
Coordinated cell polarization and mitotic spindle orientation are thought to be important for epithelial morphogenesis. Whether spindle orientation is indeed linked to epithelial morphogenesis and how it is controlled at the molecular level is still unknown. Here, we show that the NuMA- and Gα-binding protein LGN is re...
10.1038/nrc3169
This study provides evidence that LGN, together with Gα I and NUMA, regulates the orientation of mitotic spindles in mammalian cells.
10.1073/pnas.0801788105
62,299,698
Molecular dynamics and hybrid quantum mechanics/molecular mechanics have been used to investigate the mechanisms of + AdoMet methylation of protein-Lys-NH 2 catalyzed by the lysine methyltransferase enzymes: histone lysine monomethyltransferase SET7/9, Rubisco large-subunit dimethyltransferase, viral histone lysine tri...
10.1038/nrd2974
This work provides a detailed theoretical basis to explain the substrate specificity of the protein lysine methyltransferases.
10.1126/science.287.5454.848
61,918,457
Hereditary paraganglioma (PGL) is characterized by the development of benign, vascularized tumors in the head and neck. The most common tumor site is the carotid body (CB), a chemoreceptive organ that senses oxygen levels in the blood. Analysis of families carrying the PGL1 gene, described here, revealed germ line muta...
10.1038/nrc1013
Identification of SDHD as the susceptiblity gene for 11q-linked hereditary paraganglioma families. SDHD is the first nuclear gene that encodes a mitochondrial component and that has been shown to be involved in a cancer-susceptiblity syndrome.
10.1126/scitranslmed.aad7118
104,352,136
PD pathway blockade elicits durable antitumor responses in a subset of patients with a broad spectrum of cancers.
10.1038/nri.2017.49
This is a recent review on PD1 and PDL1 that describes checkpoint blockade mechanisms, manipulation of PD1–PDL1 signalling and the influence of checkpoint blockade on therapeutic outcomes.
10.4049/jimmunol.181.7.4733
20,362,733
Abstract Th1 and Th17 T cells are often colocalized in pathological environments, yet Th1-derived IFN-γ inhibits Th17 cell development in vitro. We explored the physiologic basis of this paradox in humans. In this study, we demonstrate increased the number of CD4+ and CD8+ IL-17+ T cells in skin lesions of psoriasis. F...
10.1038/nri.2017.49
This study shows how T H 1 cell-derived IFNγ can induce human IL-17 + T cells to migrate into an inflammatory microenvironment.
10.1158/0008-5472.465.65.2
132,877,182
Abstract Ovarian carcinomas have a poor prognosis, often associated with multifocal i.p. dissemination accompanied by intense neovascularization. To examine tumor angiogenesis in the tumor microenvironment, we studied malignant ascites and tumors of patients with untreated ovarian carcinoma. We observed that malignant ...
10.1038/nri.2017.49
This paper describes a novel angiogenesis strategy in which hypoxia-induced VEGF and CXCL12 production in ovarian cancer cells synergistically induces angiogenesis and vascular endothelial cell survival.
10.1084/jem.190.10.1417
29,092,000
We have analyzed the presence of immature and mature dendritic cells (DCs) within adenocarcinoma of the breast using immunohistochemistry. Immature DCs were defined by expression of CD1a-, Langerin-, and intracellular major histocompatibility complex class II–rich vesicles. Mature DCs were defined by expression of CD83...
10.1038/nri.2017.49
This study demonstrates that the intratumoural and peritumoural localization of immature myeloid DCs is mediated by the CCL20–CCR6 chemokine axis in breast cancer tissue.
10.1158/0008-5472.can-04-1987
123,459,287
Abstract CD4+CD25+ regulatory T cells (Tregs) mediate peripheral T-cell homeostasis and contribute to self-tolerance. Their homeostatic and pathologic trafficking is poorly understood. Under homeostatic conditions, we show a relatively high prevalence of functional Tregs in human bone marrow. Bone marrow strongly expre...
10.1038/nri.2017.49
This study helps to explain why cancers metastasize to the bone marrow. It shows that T reg cells traffic into the bone marrow via CXCR4-mediated signalling and create an immunosuppressive microenvironment that supports tumour metastasis.
10.1182/blood-2001-12-0196
123,193,906
Abstract Natural killer T (NKT) cells are important regulators of the immune system, but their trafficking machinery, including expression of chemokine receptors, has been poorly defined. Unlike other conventional T-cell populations, we show that most NKT cells express receptors for extralymphoid tissue or inflammation...
10.1038/nri.2017.49
This paper defines the differential chemokine receptor expression of different NKT cell subsets that facilitates their migration into inflammatory tissues.
10.1084/jem.20031462
123,193,832
CD1d-restricted Vα24-Jα18–invariant natural killer T cells (iNKTs) are potentially important in tumor immunity. However, little is known about their localization to tumors. We analyzed 98 untreated primary neuroblastomas from patients with metastatic disease (stage 4) for tumor-infiltrating iNKTs using TaqMan® reverse ...
10.1038/nri.2017.49
This is one of the few papers showing how NKT cells can migrate into tumours in response to CCL2.
10.4049/jimmunol.174.9.5490
17,833,527
Abstract Breast and kidney-expressed chemokine (BRAK) CXCL14 is a new CXC chemokine with unknown function and receptor selectivity. The majority of head and neck squamous cell carcinoma (HNSCC) and some cervical squamous cell carcinoma do not express CXCL14 mRNA, as opposed to constitutive expression by normal oral squ...
10.1038/nri.2017.49
References 61 and 62 highlight the importance of CXCL14 and CCL20 in myeloid DC migration into and activation within tumours.
10.1084/jem.20141836
62,585,857
Pulmonary metastasis of breast cancer cells is promoted by a distinct population of macrophages, metastasis-associated macrophages (MAMs), which originate from inflammatory monocytes (IMs) recruited by the CC-chemokine ligand 2 (CCL2). We demonstrate here that, through activation of the CCL2 receptor CCR2, the recruite...
10.1038/nri.2017.49
This study demonstrates the importance of CCL2 signalling in macrophage tumour biology.
10.1158/1078-0432.ccr-06-2073
62,671,480
Abstract Purpose: The role of macrophages in tumorigenesis is complex because they can both prevent and promote tumor development. Experimental Design: Four hundred forty-six colorectal cancer specimens were stained with the pan-monocyte/macrophage marker CD68, and average infiltration along the tumor front was semiqua...
10.1038/nri.2017.49
This paper reveals that CD68 + macrophage infiltration is positively associated with a better clinical outcome, and that the pro-tumorigenic and antitumorigenic roles of macrophages may depend on cancer cell–macrophage subset contact.
10.1182/blood-2011-02-338780
82,221,553
Abstract The aim of this study was to evaluate the nonchemotactic function of CCL18 on human dendritic cells (DCs). In different protocols of DC differentiation, CCL18 was highly produced, suggesting that it may constitute a mandatory mediator of the differentiation process. Differentiation of monocytes from healthy su...
10.1038/nri.2017.49
This study is one of the first to define a non-chemotactic effect of CCL18 on DCs; CCL18 promotes the differentiation of tolerogenic DCs, and this immunosuppressive effect may occur within tumours.
10.1158/1078-0432.ccr-07-2025
125,338,559
Abstract Purpose: Specific chemokines and their respective receptors have been implicated in distant tumor cell metastasis. Cutaneous melanoma has a distinct pattern of metastasis, preferentially targeting the submucosa of the small intestine. However, the underlying pathogenic mechanism remains unknown. Migration of C...
10.1038/nri.2017.49
This study shows that in cutaneous melanoma cells, active CCR9 signalling may help to promote metastasis to the small intestine.
10.1158/0008-5472.can-15-1938
59,302,843
Abstract Infiltration of tumors with effector T cells is positively associated with therapeutic efficacy and patient survival. However, the mechanisms underlying effector T-cell trafficking to the tumor microenvironment remain poorly understood in patients with colon cancer. The polycomb repressive complex 2 (PRC2) is ...
10.1038/nri.2017.49
References 172 and 173 highlight a novel tumour-intrinsic mechanism in which epigenetic repression of chemokine production is mediated by PRC2, which regulates antitumour T cell infiltration, and thus tumour immunity and immunotherapy.
10.1073/pnas.0703182104
121,973,700
Structural transitions of RNA between alternate conformations with similar stabilities are associated with important aspects of cellular function. Few techniques presently exist that are capable of monitoring such transitions and thereby provide insight into RNA dynamics and function at atomic resolution. Riboswitches ...
10.1038/nmeth.1735
Time-resolved NMR spectroscopy is used to monitor conformational changes in an aptamer domain of an RNA riboswitch that are triggered following ligand binding.
10.1126/science.290.5500.2306
59,323,339
Understanding how DNA binding proteins control global gene expression and chromosomal maintenance requires knowledge of the chromosomal locations at which these proteins function in vivo. We developed a microarray method that reveals the genome-wide location of DNA-bound proteins and used this method to monitor binding...
10.1038/nrg2270
This paper introduced the ChIP–chip technique, used here to map Gal4 and Ste12 binding sites in the yeast genome.
10.1126/science.1112178
62,026,128
The positioning of nucleosomes along chromatin has been implicated in the regulation of gene expression in eukaryotic cells, because packaging DNA into nucleosomes affects sequence accessibility. We developed a tiled microarray approach to identify at high resolution the translational positions of 2278 nucleosomes over...
10.1038/nrg2270
This study profiled nucleosome positions at high resolution across most of chromosome 3 of the S. cerevisiae genome with MNase digestion followed by hybridization to DNA microarrays.
10.1126/science.1147535
38,209,980
MicroRNAs (miRNAs) repress hundreds of target messenger RNAs (mRNAs), but the physiological roles of specific miRNA-mRNA interactions remain largely elusive. We report that zebrafish microRNA-430 (miR-430) dampens and balances the expression of the transforming growth factor–β (TGF-β) Nodal agonist squint and the TGF-β...
10.1038/nrm2868
This paper reveals a requirement for a miRNA in dampening and balancing agonist–antagonist pairs.
10.1002/ijc.2910250409
102,916,390
Abstract A rapid in vivo clearance of tumor cells was found in normal mice following intravenous inoculation of [ 125 l]dUrd‐labelled YAC‐1 and RBL‐5 cultured cell lines derived from lymphomas. The ability of mice to eliminate tumor cells from spleen, liver and lungs during the first 4 h, as evaluated by the recovery o...
10.1038/nrc928
An early and clear description of the natural activity of NK cells against tumour cells in vivo
10.1084/jem.162.6.1745
60,509,402
Three independent variants with a profound reduction of cell surface H-2 have been selected from the C57BL/6 mouse-derived RBL-5 and EL-4 T lymphomas. After subcutaneous inoculation of low cell doses in syngeneic mice, the H-2- variants failed to grow out, whereas the H-2+ control lines showed progressive growth. No di...
10.1038/nrc928
A selection of mouse lymphoma variants that lacked H-2 first illustrated the concept of NK cells recognizing 'missing-self' in vivo
10.1002/eji.1830251246
101,870,608
Abstract Adaptive immune surveillance by T cells against infections and tumors depends on the presence of antigenic peptides presented by major histocompatibility complex (MHC) molecules. If antigenic tumor‐specific peptides or MHC class I molecules are absent, the adaptive T cell immune response fails. Natural killer ...
10.1038/nrc928
The first demonstration that perforin is a major effector pathway used by NK cells to eliminate MHC class-I-deficient tumours in vivo
10.1084/jem.191.4.661
125,332,266
Natural tumor surveillance capabilities of the host were investigated in six different mouse tumor models where endogenous interleukin (IL)-12 does or does not dictate the efficiency of the innate immune response. Gene-targeted and lymphocyte subset–depleted mice were used to establish the relative importance of natura...
10.1038/nrc928
Striking demonstration of the role of NK1.1 + cells in natural protection from chemical carcinogen-induced tumour initiation.
10.1126/science.1068440
20,822,065
T cells that accompany allogeneic hematopoietic grafts for treating leukemia enhance engraftment and mediate the graft-versus-leukemia effect. Unfortunately, alloreactive T cells also cause graft-versus-host disease (GVHD). T cell depletion prevents GVHD but increases the risk of graft rejection and leukemic relapse. I...
10.1038/nrc928
Recipients of MHC-mismatched transplants display NK-cell alloreactivity that eliminates leukaemia relapse, prevents graft rejection and protects patients against graft versus host disease. A beautiful demonstration of how new knowledge about NK-cell receptors for MHC class I can pave the way for effective immunotherapy...
10.1084/jem.186.7.1129
42,516,107
Limited information is available on the surface molecules that are involved in natural killer (NK) cell triggering. In this study, we selected the BAB281 monoclonal antibody (mAb) on the basis of its ability to trigger NK-mediated target cell lysis. BAB281 identified a novel NK cell–specific surface molecule of 46 kD (...
10.1038/nrc928
First decription of a new family of natural cytotoxicity receptors on NK cells that have a key role in non-MHC-restricted cytolysis.