Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “instructive signals”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources
PubMed2005

TLR ligands can activate dendritic cells to provide a MyD88-dependent negative signal for Th2 cell development.

During infection, CD4(+) Th cell responses polarize to become primarily Th1 or Th2. Th1 cells, which make IFN-gamma, are crucial for immunity to many bacterial and protozoal infections, whereas Th2 cells, which make IL-4, IL-5, and IL-13, are important for resistance to helminth infections. Polarized Th1 responses are induced by dendritic cells (DCs), which respond to pathogen-derived TLR ligands to produce IL-12 and related cytokines that are instrumental in Th1 cell outgrowth, and coordinately process and present Ag in the context of MHC class II to activate naive Th cells. In this study we show that in addition to providing positive signals for Th1 cell development, mouse DCs activated by TLR engagement can also provide a potent negative signal that prevents the development of Th2 cells. Production of this signal, which is not IL-12, IL-18, IL-23, IL-27, or IFN-gamma and is not provided via Th1 cells, is dependent upon a MyD88-dependent, TNF receptor-associated factor-6-independent signaling pathway in DCs. The signal is released from DCs in response to activation via TLR ligands and exerts an effect directly on Th cells rather than through a third-party cell. Our findings indicate that DCs can provide potent negative as well as positive instruction for Th response polarization, and that these instructional signals are distinct and independent.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Combinatorial signaling codes for the progressive determination of cell fates in the Drosophila embryonic mesoderm.

Mesodermal progenitors arise in the Drosophila embryo from discrete clusters of lethal of scute (l'sc)-expressing cells. Using both genetic loss-of-function and targeted ectopic expression approaches, we demonstrate here that individual progenitors are specified by the sequential deployment of unique combinations of intercellular signals. Initially, the intersection between the Wingless (Wg) and Decapentaplegic (Dpp) expression domains demarcate an ectodermal prepattern that is imprinted on the adjacent mesoderm in the form of a L'sc precluster. All mesodermal cells within this precluster are competent to respond to a subsequent instructive signal mediated by two receptor tyrosine kinases (RTKs), the Drosophila epidermal growth factor receptor (DER) and the Heartless (Htl) fibroblast growth factor receptor. By monitoring the expression of the diphosphorylated form of mitogen-associated protein kinase (MAPK), we found that these RTKs are activated in small clusters of cells within the original competence domain. Each cluster represents an equivalence group because all members initially resemble progenitors in their expression of both L'sc and mesodermal identity genes. Thus, localized RTK activity induces the formation of mesodermal equivalence groups. The RTKs remain active in the single progenitor that emerges from each cluster under the subsequent inhibitory influence of the neurogenic genes. Moreover, DER and Htl are differentially involved in the specification of particular progenitors. We conclude that distinct cellular identity codes are generated by the combinatorial activities of Wg, Dpp, EGF, and FGF signals in the progressive determination of embryonic mesodermal cells.

Animals↗
PubMed1988

Neuronal activity in cortical motor areas related to ipsilateral, contralateral, and bilateral digit movements of the monkey.

1. Single cell activity was studied in the precentral (PCM), premotor (PM), and supplementary (SMA) motor cortex of the monkey to compare magnitudes of activity changes in relation to ipsilateral, contralateral, and bilateral digit movements. 2. Three Japanese monkeys were trained to press a small key with the right or left hand, or with both hands, in accordance with visual instruction signals given 2.6-5.4 s before a visual movement-trigger signal. Great care was taken to train the animal to use only the required part of the limb. As a result of extensive training, electromyographic (EMG) studies revealed that muscle activities before the key press were limited to the digit and hand muscles of the limb instructed to move. No overt increase or decrease in activity was detectable in the proximal limb or body muscles in relation to the key-press movements or instructions. 3. Even though the movement was thus limited to distal forelimb, distinct ipsilateral relationships were observed in 8.2% of the task-related PCM neurons. They changed their activity before ipsilateral and bilateral (but not before contralateral) key press. 4. A majority of the neurons recorded from the digit area of PCM (mostly limited to the anterior bank of the central sulcus) exhibited a contralateral relationship; namely the activity increased or decreased before the onset of the contralateral and bilateral key-press movements. In most of them, the magnitudes of the activity changes before the contralateral and bilateral movements were similar. 5. In proximal limb and trunk areas of PCM and also in the somatosensory cortex, no neurons were found to exhibit distinct relations to any of the key-press movements. 6. In both SMA and PM, a number of neurons exhibited relationships of the type never or only rarely observed in the primary motor cortex. Thirty-seven percent of SMA and 62% of PM neurons exhibited premovement activity changes before all of the key-press movements. The movement-specific type of activity was observed in 28% of SMA and 16% of PM neurons. In these neurons, the activity changes were observed in relation to only one of the right or left key-press movements or exclusively in relation to the bilateral key press. Neuronal activity resembling the majority of the PCM neurons (contralateral type) was observed in 31% of SMA and 13% of PM neurons. 7. Instruction-induced changes in activity were more often found in the secondary than in the primary motor area.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Delta-notch signaling and Drosophila cell fate choice.

Delta and Notch encode cell surface proteins that function in a wide variety of cell fate specification events during oogenesis, embryogenesis, and metamorphosis in Drosophila melanogaster. Various lines of evidence imply that Delta and Notch proteins function as signal and receptor in cellular interactions required for the partitioning of fates among cells within equivalence groups in many developmental contexts. Molecular and genetic observations provide a framework for the formulation of hypotheses concerning the mechanisms by which the Delta ligand and Notch receptor interact and the Delta-Notch signal is transduced in a manner that can affect the adoption of distinct fates by different cells. In particular, emerging evidence regarding the expression and function of Delta and Notch during development also raise possible alternatives to the currently favored hypothesis that Delta-Notch interactions generate instructive signals that mediate a process termed lateral inhibition.

Animals↗
PubMed1999

The cell surface-associated intercellular C-signal induces behavioral changes in individual Myxococcus xanthus cells during fruiting body morphogenesis.

Fruiting body formation in Myxococcus xanthus depends on ordered changes in cell movements from swarming to aggregation in response to starvation. We show that appropriately starved individual cells change behavior during fruiting body formation. Specifically, from the time of initiation of aggregation, individual wild-type cells began to move with increased gliding speeds, the duration of the mean gliding interval increased, and the stop frequency decreased whereas the duration of the mean stop interval and the reversal frequency remained unchanged. Mutants lacking the cell surface-associated, intercellular C-signal (csgA mutants) failed to aggregate. Likewise, appropriately starved individual csgA cells did not change their behavior during development. In the absence of other cell-cell interactions, the motility defect of individual csgA cells was corrected in a time- and concentration-dependent manner after C-signaling was reestablished by exogenous MalE-CsgA protein. The C-signal-induced stimulation of motility depended on the cytoplasmic Frz signal transduction system. We propose that C-signal instructs cells to move with high speed and low stop and reversal frequencies into aggregation centers during development.

Bacterial Proteins↗
PubMed2006

Complement and Toll-like receptors: key regulators of adaptive immune responses.

The innate immune system provides sophisticated defense mechanisms to protect complex macroorganisms from the attack of microorganisms. Among those, the complement system and Toll-like receptors are of paramount importance to discriminate between infectious non-self and non-infectious self and to provide critical danger signals instructing adaptive immune responses. Here, we will discuss recent advances in our understanding of the mechanisms underlying complement and TLR-mediated regulation of adaptive immunity. We will focus on the regulation of T cell immunity and discuss recent findings on the cross-talk between complement receptor and TLR signaling pathways. Such cross-talk is likely to affect the outcome of infections with intracellular pathogens, as well as the initiation and maintenance of aberrant immune responses leading to autoimmunity and atopy.

Animals↗
PubMed2000

FGF10 is an inducer and Pax6 a competence factor for lacrimal gland development.

We investigated the mechanism of tissue induction and specification using the lacrimal gland as a model system. This structure begins its morphogenesis as a bud-like outgrowth of the conjunctival epithelium and ultimately forms a branched structure with secretory function. Using a reporter transgene as a specific marker for gland epithelium, we show that the transcription factor Pax6 is required for normal development of the gland and is probably an important competence factor. In investigating the cell-cell signaling required, we show that fibroblast growth factor (FGF) 10 is sufficient to stimulate ectopic lacrimal bud formation in ocular explants. Expression of FGF10 in the mesenchyme adjacent to the presumptive lacrimal bud and absence of lacrimal gland development in FGF10-null mice strongly suggest that it is an endogenous inducer. This was supported by the observation that inhibition of signaling by a receptor for FGF10 (receptor 2 IIIb) suppressed development of the endogenous lacrimal bud. In explants of mesenchyme-free gland epithelium, FGF10 stimulated growth but not branching morphogenesis. This suggested that its role in induction is to stimulate proliferation and, in turn, that FGF10 combines with other factors to provide the instructive signals required for lacrimal gland development.

Animals↗
PubMed1996

Parietal cortex area 5 and visuomotor behavior.

For years, area 5 of the parietal cortex was thought to be a somatic sensory structure. This view was challenged by recordings during active movements in alert behaving monkeys, which suggested that area 5 also contained populations of neurons that issued nonspecific, context-dependent "commands" about intended motor responses. Recent studies have revealed that area 5 generates a representation of the spatiotemporal form of arm movements and arm postures, although the parameter space of that representation is still controversial. They also showed that many area 5 cells are recipient to centrally generated signals about the motor relevance of external sensory signals. These new results support the hypothesis that area 5 contributes to the sensorimotor guidance of motor behavior, by contributing to the somatomotor and visuomotor transformations presumed to underlie visually guided behavior. However, area 5 appears to be less directly implicated than the premotor cortex in the process of selecting the nature of the response to instructional signals.

Animals↗
PubMed1997

Two signalling pathways specify localised expression of the Broad-Complex in Drosophila eggshell patterning and morphogenesis.

The Drosophila eggshell, which has a pair of chorionic appendages (dorsal appendages) located asymmetrically along both the anterior/posterior and dorsal/ventral axes, provides a good model to study signal instructed morphogenesis. We show that the Broad-Complex, a gene encoding zinc-finger transcription factors, is essential for the morphogenesis of dorsal appendages and is expressed in a bilaterally symmetrical pattern in the lateral-dorsal-anterior follicle cells during late oogenesis. This is induced and specified along the dorsoventral axis by an epidermal growth factor receptor signalling pathway, which includes a localised transforming growth factor-alpha like molecule, Gurken, in the oocyte and the Drosophila EGF receptor homologue, Torpedo, in the surrounding somatic follicle cells. Furthermore, the precisely localised expression of BR-C along the AP axis requires a separate signalling pathway, initiated by a transforming growth factor-beta homologue, Decapentaplegic, in nearby follicle cells. These two signalling pathways, one from the oocyte and the other from the follicle cells, co-ordinately specify patches of follicle cells to express the Broad-Complex in a unique position in respect to both major axes, which in turn directs the differentiation of the dorsal appendages in the correct position on the eggshell.

Animals↗
PubMed2004

Cellular immune response to parasitization in Drosophila requires the EBF orthologue collier.

Drosophila immune response involves three types of hemocytes ('blood cells'). One cell type, the lamellocyte, is induced to differentiate only under particular conditions, such as parasitization by wasps. Here, we have investigated the mechanisms underlying the specification of lamellocytes. We first show that collier (col), the Drosophila orthologue of the vertebrate gene encoding early B-cell factor (EBF), is expressed very early during ontogeny of the lymph gland, the larval hematopoietic organ. In this organ, Col expression prefigures a specific posterior region recently proposed to act as a signalling centre, the posterior signalling centre (PSC). The complete lack of lamellocytes in parasitized col mutant larvae revealed the critical requirement for Col activity in specification of this cell type. In wild-type larvae, Col expression remains restricted to the PSC following parasitization, despite the massive production of lamellocytes. We therefore propose that Col endows PSC cells with the capacity to relay an instructive signal that orients hematopoietic precursors towards the lamellocyte fate in response to parasitization. Considered together with the role of EBF in lymphopoiesis, these findings suggest new parallels in cellular immunity between Drosophila and vertebrates. Further investigations on Col/EBF expression and function in other phyla should provide fresh insight into the evolutionary origin of lymphoid cells.

Animals↗
PubMed2005

Characterization of innexin gene expression and functional roles of gap-junctional communication in planarian regeneration.

Planaria possess remarkable powers of regeneration. After bisection, one blastema regenerates a head, while the other forms a tail. The ability of previously-adjacent cells to adopt radically different fates could be due to long-range signaling allowing determination of position relative to, and the identity of, remaining tissue. However, this process is not understood at the molecular level. Following the hypothesis that gap-junctional communication (GJC) may underlie this signaling, we cloned and characterized the expression of the Innexin gene family during planarian regeneration. Planarian innexins fall into 3 groups according to both sequence and expression. The concordance between expression-based and phylogenetic grouping suggests diversification of 3 ancestral innexin genes into the large family of planarian innexins. Innexin expression was detected throughout the animal, as well as specifically in regeneration blastemas, consistent with a role in long-range signaling relevant to specification of blastema positional identity. Exposure to a GJC-blocking reagent which does not distinguish among gap junctions composed of different Innexin proteins (is not subject to compensation or redundancy) often resulted in bipolar (2-headed) animals. Taken together, the expression data and the respecification of the posterior blastema to an anteriorized fate by GJC loss-of-function suggest that innexin-based GJC mediates instructive signaling during regeneration.

Amino Acid Sequence↗
PubMed2004

Positive selection and lineage commitment during peripheral B-lymphocyte development.

Although it is appreciated that the antigen receptor on B cells is required for peripheral B-lymphocyte development and survival, it has been unclear whether this receptor interacts with self-antigens during development or if it signals constitutively in an antigen-independent fashion. The analysis of mutant mice in which antigen receptor signaling in B cells is either attenuated or enhanced has revealed the existence of a follicular versus marginal zone B-lymphocyte cell-fate decision. These analyses indicate that weak antigen receptor-derived signals favor marginal zone B-cell generation, and relatively strong signals favor the development of mature follicular B cells. Even stronger signals derived from the antigen receptor favor the generation of B1 B cells. This signal strength model for B-cell development supports the notion that self-antigens of varying affinity may mediate positive selection and lineage commitment. Direct evidence supporting such a view has been obtained from the analysis of antigen receptor knockin mice. Specific antigen receptors guide B cells to develop into specific lineages. Although Notch-2, nuclear factor-kappaBp50, and other genes are essential for marginal zone B-cell development, instructive signals delivered by the antigen receptor represent the primary force driving positive selection and lineage commitment in B lymphocytes.

Animals↗
PubMed2004

Neurotrophin action on a rapid timescale.

Mechanisms underlying the fast action of neurotrophins include intracellular Ca(2+) signaling, neuronal excitation, augmentation of synaptic excitation by modulation of N-methyl-d-aspartate receptor activity and control of synaptic inhibition through the regulation of the K(+)-Cl(-) cotransporter KCC2. The fastest action of brain-derived neurotrophic factor and neurotrophin-4/5 occurs within milliseconds, and involves activation of TrkB and the opening of the Na(+) channel Na(v)1.9. Through these rapid actions, neurotrophins shape neuronal activity, modulate synaptic transmission and produce instructive signals for the induction of long-term changes in the efficacy of synaptic transmission.

Animals↗
PubMed1995

Asymmetric signaling requirements for thymocyte commitment to the CD4+ versus CD8+ T cell lineages: a new perspective on thymic commitment and selection.

Differentiation of immature CD4+ CD8+ thymocytes into mature CD4+ CD8- and CD4-CD8+ T cells requires that synthesis of one or the other coreceptor molecule be terminated, a process referred to as lineage commitment. The present study has utilized a novel coreceptor reexpression assay to identify lineage commitment in immature thymocytes and has found that the MHC recognition requirements for CD4 commitment and CD8 commitment fundamentally differ from one another. Remarkably, we found that thymocyte commitment to the CD8+ lineage requires MHC class I-dependent instructional signals, whereas thymocyte commitment to the CD4+ lineage is MHC independent and may occur by default. In addition, an unanticipated relationship between lineage commitment and surface phenotype has been identified. These results are incompatible with current concepts and require a new perspective on lineage commitment and positive selection, which we refer to as asymmetric commitment.

Animals↗
PubMed2005

How do cancer cells acquire the fuel needed to support cell growth?

In this paper we consider whether the dependency of metazoan cells on extracellular signals to maintain cell survival results in an important barrier that must be overcome during carcinogenesis. It is now generally accepted that a major barrier to cancer comes from the inability of cells to enter and progress through the cell cycle in a cell-autonomous fashion. Most of the oncogenes studied over the last two decades contribute to the ability of the cancer cell to enter and progress through the cell cycle in the absence of the instructional signals normally imparted by extracellular growth factors. Over the last two decades, it has begun to be appreciated that there is a second potential barrier to transformation. It appears that all cells in multicellular organisms need extracellular signals not only to initiate proliferation, but also to maintain cell survival. Every cell in our body expresses the proteins necessary to execute its own death by apoptosis. A cell will activate this apoptotic program by default unless it receives signals from the extracellular environment that allow the cell to suppress the apoptotic machinery it expresses. It now appears that the molecular basis of this suppression lies in the signaling pathways that regulate cellular nutrient uptake and direct the metabolic fate of those nutrients.

Adenosine Triphosphate↗
PubMed2006

Molecular mechanisms of cytodifferentiation in mammalian tooth development.

The morphological stages of tooth development--bud, cap, bell, and terminal differentiation--have been known for decades. The past 10 years have seen the elucidation of many of the molecular events driving these morphogenetic stages. Signaling via the fibroblast growth factor (FGF), bone morphogenetic protein (BMP), hedgehog, and wingless protein families and their downstream transcription factors have been identified as key players in the epithelial-mesenchymal signaling loops driving tooth development. Currently the most complete description of the mechanisms in tooth development extends only through the cap stage. The body of work concerning the mechanisms directing the bell and cytodifferentiation stages is growing. This has mainly, but not exclusively, focused on the expression and effects of FGFs and BMPs in these latter stages, and is reviewed here. Additionally, recent results suggest that phenotypic proteins of both ameloblasts and odontoblasts, such as amelogenin and dentin matrix protein 2 may act as the final instructive signals in cytodifferentiation.

Ameloblasts↗
PubMed2004

Song development: in search of the error-signal.

Song development provides an opportunity to study the mechanisms of vocal learning dynamically at molecular, cellular and systems levels, and across time scales ranging from minutes to months. To exploit these opportunities one needs to identify appropriate units, types and time scales of vocal change in nearly real time. The previous chapter by Tchernikovski et al. in this volume described techniques that make this research strategy feasible by allowing us to observe the song learning process through a "temporal microscope" with variable degrees of resolution. In this chapter we summarize some of the new observations and raise hypotheses about the learning strategy of the bird. We focus on inferences that can be drawn from behavioral observations to the nature and complexity of the instructive signal that guides the vocal change (error-signal). We examine two effects: i) the emergence of syllable types and ii) changes in features within a syllable type. We found that different features of the same syllable change during different and sometimes disjointed developmental windows. We discuss the possibility that song imitation is achieved by correcting partial errors, and that features of those partial errors change adaptively during development, perhaps concurrently with changes in perception and in motor proficiency. Those hypotheses can be best examined by across levels investigation, starting from identifying critical moments in song development and recording of articulatory dynamics and neural patterns when only a few features of specific syllables undergo rapid changes. Such investigation could relate behavioral events to brain mechanisms that guide song learning from moment-to-moment and across extended periods.

Animals↗
PubMed2005

Antero-posterior patterning of the vertebrate digestive tract: 40 years after Nicole Le Douarin's PhD thesis.

This review is dedicated to the work on chick digestive tract organogenesis that Nicole Le Douarin performed as a PhD student under the direction of Etienne Wolf. I discuss how she laid the grounds for future work by establishing fate maps at somitic stages, by describing morphogenetic movements between germ layers and by pointing to signaling events between endoderm and mesoderm. Her inspiring work was extended by others, in particular at the molecular level, leading to a better understanding of antero-posterior patterning in the digestive tract. Antero-posterior patterning of endoderm is initiated at gastrulation when future anterior and posterior endoderm ingress at different times and accordingly express different genes. Plasticity is however maintained at somite stages and even later, when organ primordia can be delineated. There is a cross-talk between endoderm and mesoderm and the two layers exchange instructive signals that induce specific antero-posterior identities as well as permissive signals required for organogenesis from previously patterned fields. Recent experiments suggest that several signaling molecules involved in neural tube antero-posterior patterning are also instrumental in the digestive tract including retinoic acid and FGF4.

Animals↗