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PubMed2002

Extension, retraction and contraction in the formation of a dendritic cell dendrite: distinct roles for Rho GTPases.

The morphology of antigen-presenting dendritic cells (DC) is characterized by the possession of numerous long arborizing processes known as dendrites. The formation of these processes by DC, both in the periphery and in lymphoid organs, is believed to contribute to the remarkable efficiency with which they take up, process and present antigen to T cells. However, the process of dendrite formation and the signaling pathways that lead to the formation of these dendrites remain obscure. In this study we describe an in vitro model in which human immature DC form long processes similar to those formed in vivo. The formation of these processes involves initial attachment of a cell protrusion to the extracellular matrix substrate, and subsequent movement of the cell body away from the adhesion site, leaving behind a long slender dendrite. Dendrite formation, but not their maintenance, was found to be dependent on the activity of Rho GTPases. More specifically, Cdc42 and Rac1 were both required for the migration step of process formation, promoting cell spreading and extension. In contrast, Rho, and its downstream effector p160ROCK, regulated the release of adhesions to the substratum, and associated cellular contraction. Consequently, inhibition of Rho/p160ROCK leads to the formation of longer dendrites. DC therefore coordinate adhesion and protrusion to perform a specialized process of cellular morphogenesis, which differentiates these cells from all other cells of the immune system and may contribute to their distinctive function.

Cell Adhesion↗

PubMed1995

Dendritic reorganisation in the basal forebrain under degenerative conditions and its defects in Alzheimer's disease. I. Dendritic organisation of the normal human basal forebrain.

In the present study, the dendritic organisation of neurones in the normal human basal forebrain was analysed as a prerequisite for the evaluation of pathological changes occurring in Alzheimer's disease and related conditions (see other Arendt et al. papers in this issue). Neurones in the basal nucleus of Meynert (NbM), the nucleus of the vertical limb of the diagonal band, and the medial septal nucleus were examined after Golgi impregnation. Cells were classified according to the dendritic branching pattern and soma shape as either reticular neurones or multipolar giant neurones. The reticular type of neurones constitutes more than 90% of neurones in the BnM. Cholinergic neurones also belong to this cell type. Reticular neurones were further subdivided into four subtypes. Morphological features and arrangement of reticular basal forebrain neurones were identical to those described for "reticular formation cells" or "isodendritic" neurones. Dendritic trees of reticular neurones show a spatial orientation perpendicular to passing fibres as well as a high degree of overlap, both of which are hallmarks of "open nuclei." The qualitative classification of Golgi-impregnated basal forebrain neurones was substantiated by a computer-based three-dimensional analysis. Topologic and metric parameters of the dendritic tree were calculated for each type of neurone to characterise the degree of dendritic branching, the shape and orientation of the dendritic arborisation, the spatial extension of the dendritic tree, and soma size. The classification criteria were evaluated according to their power of discrimination between different cell types by means of a discriminant analysis. The quantitative approach applied in the present study not only provides an objective measure for the description and comparison of the structure of various types of neurones but also makes it possible to elucidate fine structural changes that might occur under pathologic conditions and that are not evident during qualitative studies alone.

Adult↗

PubMed2006

Variations in plasmacytoid dendritic cell (PDC) and myeloid dendritic cell (MDC) levels in HIV-infected subjects on and off antiretroviral therapy.

Plasmacytoid and myeloid dendritic cells are reduced in AIDS patients. The number of these circulating cells was assessed cross-sectionally and longitudinally in 27 uninfected and 72 HIV-infected subjects on and off antiretroviral therapy. The plasmacytoid dendritic cell numbers were significantly reduced in the HIV-infected subjects compared to controls (p < 0.001). This reduction correlated directly with CD4+ cell counts (p < 0.001) and inversely with viral load (p < 0.001). These associations were found to a lesser degree for the myeloid dendritic cells. Intra-assay variability of these dendritic cell counts was < 10%. Antiretroviral therapy significantly increased plasmacytoid dendritic cell (p < 0.001) and CD4+ cell (p = 0.05) counts at 8 months by 76.9% and 19%, respectively. The plasmacytoid dendritic cell levels responded more readily to viral load increases and decreases than CD4+ cells. Circulating plasmacytoid dendritic cells may provide important additional information about immune function in HIV-infected subjects receiving or not receiving antiretroviral therapy.

Adult↗

PubMed1997

GIRK1 immunoreactivity is present predominantly in dendrites, dendritic spines, and somata in the CA1 region of the hippocampus.

Electron microscopic analysis of the CA1 region of the rat hippocampus revealed that specific immunoreactivity (IR) for a G protein-gated, inwardly rectifying potassium channel (GIRK1) was present exclusively in neurons and predominantly located in spiny dendrites of pyramidal cells. Within stratum lacunosum-moleculare and the superficial stratum radiatum, GIRK1-IR was often present immediately adjacent to asymmetric (excitatory-type) postsynaptic densities in dendritic spines. The subcellular localization of GIRK1-IR in the Golgi apparatus of pyramidal cell somata and in the plasma membrane of dendrites and dendritic spines confirms the hypothesis that GIRK1 is synthesized by pyramidal cells and transported to the more distal dendritic processes. G protein-coupled receptor activation of a dendritic potassium conductance would attenuate the propagation of excitatory synaptic inputs and thereby produce postsynaptic inhibition. Thus, these results show that the GIRK family of channels joins the list of voltage-sensitive channels now known to be expressed in dendritic spines.

Amino Acid Sequence↗

PubMed2005

Vaccination with dendritic cells transfected with BAK and BAX siRNA enhances antigen-specific immune responses by prolonging dendritic cell life.

Dendritic cell-based vaccines have become an important approach for the treatment of malignancies. Numerous techniques have recently been designed to optimize dendritic cell activation, tumor antigen delivery to dendritic cells, and induction of tumor-specific immune responses in vivo. Dendritic cells (DCs), however, have a limited life span because they are subject to apoptotic cell death mediated by T cells, hindering their long-term ability to prime antigen-specific T cells. Small interfering RNA targeting Bak and Bax antiapoptotic proteins can be used to allow transfected DCs to resist killing by T cells in vivo. In this study, we show that human papillomavirus E7-loaded dendritic cells transfected with BAK/BAX siRNA downregulate Bak and Bax protein expression and become resistant to killing by T cells, leading to enhanced E7-specific CD8+ T cell activation and antitumor effects in vivo. More importantly, we found that vaccination with E7-loaded DCs transfected with BAK/BAX siRNA was capable of generating a strong therapeutic effect in vaccinated mice, compared with DCs transfected with control siRNA. Our data indicate that transfection of dendritic cells with BAK/BAX siRNA represents a plausible strategy for enhancing dendritic cell-based vaccine potency.

Animals↗

PubMed2004

Activity affects dendritic shape and synapse elimination during steroid controlled dendritic retraction in Manduca sexta.

Insect metamorphosis is a compelling example for dendritic and synaptic remodeling as larval and adult behaviors place distinct demands on the CNS. During the metamorphosis of the moth, Manduca sexta, many larval motoneurons are remodeled to serve a new function in the adult. During late larval life, steroid hormones trigger axonal and dendritic regression as well as larval synapse elimination. These regressive events are accompanied by stereotypical changes in motor behavior during the so-called wandering stages. Both normally occurring changes in dendritic shape and in motor output have previously been analyzed quantitatively for the individually identified motoneuron MN5. This study tested whether activity affected steroid-induced dendritic regression and synapse disassembly in MN5 by means of chronically implanted extracellular electrodes. Stimulating MN5 in vivo in intact, normally developing animals during a developmental period when it usually shows no activity significantly slowed the regression of high-order dendrites. Both physiological and anatomical analysis demonstrated that reduced dendritic regression was accompanied by a significant reduction in larval synapse disassembly. Therefore, steroid-induced alterations of dendritic shape and synaptic connectivity are modified by activity-dependent mechanisms. This interaction might be a common mechanism for rapid adjustments of rigid, inflexible, hormonal programs.

Action Potentials↗

PubMed2000

Subcellular compartmentalization of a potassium channel (Kv1.4): preferential distribution in dendrites and dendritic spines of neurons in the dorsal cochlear nucleus.

Voltage-dependent ion channels have specific patterns of distribution along the neuronal plasma membrane of dendrites, cell bodies and axons, which need to be unravelled in order to understand their contribution to neuronal excitability and firing patterns. We have investigated the subcellular compartmentalization of Kv1.4, a transient, fast-inactivating potassium channel, in fusiform cells and related interneurons of the rat dorsal cochlear nucleus. A polyclonal antibody which binds to a region near the N-terminus domain of a Kv1.4 channel was raised in rabbits. Using a high-resolution combination of immunocytochemical methods, Kv1.4 was localized mainly in the apical dendritic trunks and cell bodies of fusiform cells, as well as in dendrites and cell bodies of interneurons of the dorsal cochlear nucleus, likely cartwheel cells. Quantitative immunogold immunocytochemistry revealed a pronounced distal to proximal gradient in the dendrosomatic distribution of Kv1. 4. In plasma membrane localizations, Kv1.4 was preferentially present in dendritic spines, either in the spine neck or in perisynaptic locations, always away from the postsynaptic density. These findings indicate that Kv1.4 is largely distributed in dendritic compartments of fusiform and cartwheel cells of the dorsal cochlear nucleus. Its preferential localization in dendritic spines, where granule cell axons make powerful excitatory synapses, suggests a role for this voltage-dependent ion channel in the regulation of dendritic excitability and excitatory inputs.

Amino Acid Sequence↗

PubMed2003

Kalirin, a multifunctional Rho guanine nucleotide exchange factor, is necessary for maintenance of hippocampal pyramidal neuron dendrites and dendritic spines.

The structures of dendritic spines and the dendritic tree, key determinants of neuronal function, are regulated by diverse inputs that affect many scaffolding and signaling molecules. Nevertheless, here we show that reduced expression of a single gene results in loss of dendritic spines and a decrease in dendritic complexity. Kalirin, a dual Rho GDP-GTP exchange factor, causes spine formation when overexpressed. Reduced expression of Kalirin in CA1 hippocampal neurons resulted in a reduction in linear spine density, with dispersion of postsynaptic density markers and elimination of presynaptic endings. Simplification of the apical dendritic tree preceded simplification of basal dendrites. Pyramidal cell axons were not dramatically altered. Although many factors determine dendrite shape and spine formation, expression of Kalirin is necessary for the normal function of these many regulatory elements.

Animals↗

PubMed1991

CD45 epitope mapping of human CD1a+ dendritic cells and peripheral blood dendritic cells.

The authors studied the pattern of leukocyte common antigen (CD45) epitope expression on dendritic cells in sections of human epidermis, tonsillar epithelium, dermatopathic lymph nodes, and in isolates from blood. The monoclonal antibodies (MAb) used were specific for all known CD45 epitopes, including the seven different CD45 common epitopes as well as the four known CD45R epitopes (two CD45RA, one CD45RB, and one CD45RO). Dendritic cells in all sites were uniformly reactive for the CD45 common epitopes tested except 2B11, which may recognize a CD45R rather than CD45 epitope. By single-label immunoperoxidase and double-label immunofluorescence epitope mapping of CD1a+ dendritic cells in tissue sections, it was generally difficult or impossible to detect expression of CD45RA, CD45RB, CD45RO, or 2B11. In blood dendritic cells, however, low levels of these CD45R epitopes were detected consistently using single-label immunoperoxidase staining of cytocentrifuge preparations. Monocytes were similar to blood dendritic cells except that the staining with MAb to CD45RO and 2B11 was slightly stronger. The authors conclude that dendritic cells differ from most subpopulations of lymphocytes in that CD45 common epitopes are readily detectable but the existing RA, RB, and RO epitopes are either undetectable or expressed at relatively low levels. These studies raise the possibility that CD1a+ dendritic cells may express a novel dominant CD45 isoform.

Antigens, CD↗

PubMed2006

Different dendrite and dendritic spine alterations in basal and apical arbors in mutant human amyloid precursor protein transgenic mice.

The extracellular deposition of amyloid-beta peptide (Abeta) in brain parenchyma is one of the characteristic features of Alzheimer's disease and is suggested to induce reactive and degenerative changes in neuronal cell bodies, axons and dendritic processes. In particular, within and in close proximity to amyloid plaques, distinctive morphological alterations have been observed, including changes in neurite trajectory and decreases in dendritic diameter and in spine density. Apart from these plaque-associated focal aberrations, little is known regarding modifications of the global dendritic morphology including the detailed and comparative quantitative analysis of apical and basal arbors. The objective of the present study was to investigate the effects of amyloid plaque deposition and elevated soluble Abeta on neuronal morphology in mutant human amyloid precursor protein (hAPP) transgenic mice (line Tg2576; [K. Hsiao, P. Chapman, S. Nilsen, C. Eckman, Y. Harigaya, S. Younkin, F. Yang, G. Cole, Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice, Science 274 (1996) 99-102]). Retrogradelly labeled callosal-projecting pyramidal cells in the primary somatosensory cortex were three-dimensionally analyzed. Although basal dendrites remained unaffected, analysis of apical trees revealed a number of unambiguous morphological changes. Thus, in TG2576 mice, the apical arbors were shortened in total length and less branched. Furthermore, the diameter of proximal dendritic segments was increased whereas that of distal segments was reduced. Analysis of spine numbers and distribution on basal and apical trees demonstrated a significant reduction in spine densities along the whole course of dendrites. The findings suggest that Abeta-related pathology induces morphological aberrations in basal and apical arbors to different degrees which are unrelated to direct plaque-associated changes.

Amyloid beta-Protein Precursor↗

PubMed1989

Deprived somatosensory-motor experience in stumptailed monkey neocortex: dendritic spine density and dendritic branching of layer IIIB pyramidal cells.

Infant macaque monkeys (Macaca arctoides) were individually raised to age 6 months in large clear cubes built into one wall of a control colony that allowed them visual access to it but not tactile contact. The two deprivation conditions (Cond 2 and Cond 3) were equal both in physical size and with respect to partial social isolation. They differed in the degree of somatosensory-motor opportunity available during development in that the Cond 2 chamber was empty, whereas Cond 3 contained ladders, a trapeze, and play objects. Four monkeys from each of these conditions were compared with four colony-reared (Cond CR) monkeys. Neuroanatomical changes were evaluated by using light microscopy in Golgi-Cox-stained neocortex. Dendritic spines on the apical shafts of layer IIIB pyramidal cells were counted in primary motor (MI), somatosensory (SI), and visual (area 17, V1) cortical regions. Layer IIIB pyramidal neurons with somas of medium size were selected from each cortical region and the density of apical dendritic spines determined. The basilar dendritic branches of these same neurons were traced, and the dendritic branching complexity was assessed in order to compare the sensitivity of the dendritic spine and branching measures consequent to deprived rearing. The number of apical dendritic spines was significantly reduced in Cond 2 when compared with either Cond 3 or Cond CR (which did not differ from each other). This occurred in both MI and SI cortex, but not in the visual cortex, the region used as a control for a global brain effect. Branching complexity measured on the same pyramidal neurons was reduced only in MI cortex of Cond 2. These results show spine density, a more direct measure of neuronal connectivity, to be the more sensitive measure of early environmental deprivation. Also, the enriched environment provided by Cond 3 relative to Cond 2 offset the effect of partial social isolation such that both morphometric measures had values comparable to Cond CR monkeys.

Animals↗

PubMed2004

The interactions between human dendritic cells and microbes; possible clinical applications of dendritic cells.

The dendritic cells comprise several subsets that induce and regulate the immune responses against foreign and self-antigens, and that can therefore function as initiators of protective immunity and inducers of central or peripheral tolerance. The different subpopulations of dendritic cells interact with and also influence other cell populations of the immune system, such as T and B lymphocytes and natural killer cells. The factors that determine the given dendritic cell functions depend on the state of maturation and the local microenvironment. The interactions between dendritic cells and microorganisms are rather complex, but progress in the past few years has shed light on several aspects of these interactions. This review lays emphasis on the interactions between human dendritic cells, important components of the intima of arterial specimens at areas predisposed to atherosclerotic lesions, and Chlamydia pneumoniae and cytomegalovirus, the human pathogens most strongly implicated in the development of atherosclerosis. In addition, several examples of the potential clinical applications of dendritic cells are described.

Arteriosclerosis↗

PubMed1979

Quantitative analysis of dendritic branching. I. Simple formulae for the quantitative analysis of dendritic branching.

Dendritic branching of neurons may be quantitatively studied using applications of graph theory. Dendritic ramifications may be considered as 'forests' of planted, stemmed, binary 'trees' with simple mathematical properties. Two fundamental numbers, that of dendritic tips and that of dendritic stems, usually suffice to quantify the dendritic branching of one neuron as, in most cases, they allow the computation of all other numbers of dendritic points and segments.

Animals↗

PubMed2004

Differential expression and dendritic transcript localization of Shank family members: identification of a dendritic targeting element in the 3' untranslated region of Shank1 mRNA.

Shank proteins are scaffolding proteins in the postsynaptic density of excitatory synapses in the mammalian brain. In situ hybridization revealed that Shank1/SSTRIP and Shank2/ProSAP1 mRNAs are widely expressed early in postnatal brain development whereas Shank3/ProSAP2 expression increases during postnatal development especially in the cerebellum and thalamus. Shank1 and Shank3 (but not Shank2) mRNAs are present in the molecular layers of the hippocampus, consistent with a dendritic transcript localization. Shank1 and Shank2 transcripts are detectable in the dendritic fields of Purkinje cells, whereas Shank3 mRNA is restricted to cerebellar granule cells. The appearance of dendritic Shank mRNAs in cerebellar Purkinje cells coincides with the onset of dendrite formation. Expression of reporter transcripts in hippocampal neurons identifies a 200-nucleotide dendritic targeting element (DTE) in the Shank1 mRNA. The widespread presence of Shank mRNAs in dendrites suggests a role for local synthesis of Shanks in response to stimuli that induce alterations in synaptic morphology.

3' Untranslated Regions↗

PubMed1985

Signal enhancement in distal cortical dendrites by means of interactions between active dendritic spines.

Pyramidal neurons in the cerebral cortex characteristically give rise to an apical dendrite, whose distal dendritic branches in layer I are covered with spines. These spines are known to be sites of synaptic connections, but the physiological properties of the spines and the functional significance of their responses are still largely unknown. The main function attributed thus far to these synaptic responses, situated at a great distance from the neuronal cell body, is slow background modulation of impulse output in the axon. In pursuing computer simulation analysis of electrical properties of dendrites, we have obtained results suggesting interactions between distal dendritic spines. If the heads of dendritic spines have excitable membrane properties, the spread of current from one or several spines could bring adjacent spines to their thresholds for impulse generation. This could give rise to a sequence of spine head action potentials, representing a saltatory propagation, from one or more excitable spine heads to nearby excitable spine heads, in the distal dendritic branches. Both the amplification due to several spine action potentials and the possibility of propagation into more proximal branches would increase the efficacy of distal synaptic inputs. Because of nonlinear dependence upon several modifiable parameters (such as spine stem resistance and membrane excitability) and upon the spatio-temporal pattern of synaptic input, such contingent synaptic enhancement would be particularly relevant to cortical functions underlying information processing and to plasticity underlying learning and memory.

Dendrites↗

PubMed2002

MAP2 is required for dendrite elongation, PKA anchoring in dendrites, and proper PKA signal transduction.

Microtubule-associated protein 2 (MAP2) is a major component of cross-bridges between microtubules in dendrites, and is known to stabilize microtubules. MAP2 also has a binding domain for the regulatory subunit II of cAMP-dependent protein kinase (PKA). We found that there is reduction in microtubule density in dendrites and a reduction of dendritic length in MAP2-deficient mice. Moreover, there is a significant reduction of various subunits of PKA in dendrites and total amounts of various PKA subunits in hippocampal tissue and cultured neurons. In MAP2-deficient cultured neurons, the induction rate of phosphorylated CREB after forskolin stimulation was much lower than in wild-type neurons. Therefore, MAP2 is an anchoring protein of PKA in dendrites, whose loss leads to reduced amount of dendritic and total PKA and reduced activation of CREB.

Animals↗

PubMed1998

No evidence for disruption of normal patterns of mRNA localization in dendrites or dendritic transport of recently synthesized mRNA in FMR1 knockout mice, a model for human fragile-X mental retardation syndrome.

Recent studies have revealed that FMRP, the gene product of the fragile-X gene FMR1, is an RNA-binding protein. These and other data have led to the idea that FMRP may play a role in targeting mRNAs for transport to synaptic sites. The present study evaluated whether a null mutation of FMR1 disrupts the patterns of localization of three mRNAs that are present constitutively in dendrites (the mRNAs for MAP2, CAMII kinase and dendrin), or disrupt the rapid dendritic transport of the mRNA for activity-regulated cytoskeletal protein (ARC), coded for by an immediate-early gene. In situ hybridization analyses revealed that the patterns of mRNA localization in dendrites and the dendritic transport of ARC mRNA are indistinguishable from normal in FMR1 knockout mice. These results indicate that FMRP does not play an obligatory role in targeting this set of mRNAs to dendrites, although it might be involved in targeting other dendritic mRNAs yet to be identified.

Animals↗

PubMed2002

Sézary syndrome patients demonstrate a defect in dendritic cell populations: effects of CD40 ligand and treatment with GM-CSF on dendritic cell numbers and the production of cytokines.

Sézary syndrome (SzS) is an advanced form of cutaneous T-cell lymphoma associated with involvement of the peripheral blood by malignant T cells. The disease is defined by impaired cell-mediated immunity and the production of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), possibly as a result of deficient IL-12 production. To understand the mechanism of this impairment, we examined the composition and function of dendritic cells and monocytes in the blood of SzS patients with different levels of peripheral blood tumor burden. Consistent with our previous observations, numbers of monocytes in SzS patients were comparable to numbers observed in healthy donors. In contrast, decreased IL-12 production correlated with a decrease in the numbers of CD11c(+) dendritic cells, which was particularly profound among patients with medium (20%-50% circulating malignant T cells) and high (more than 50% circulating malignant T cells) tumor burden. Furthermore, CD123(+) dendritic cells, major producers of IFN-alpha, were significantly diminished in SzS patients, regardless of the level of tumor burden. Granulocyte macrophage-colony-stimulating factor-treated patients experienced an increase in the number of dendritic cells but not in IFN-alpha or IL-12 production. However, in vitro stimulation of peripheral blood mononuclear cells from SzS patients with rCD40L and IFN-gamma significantly increased the production of IL-12. Thus, our results demonstrate a profound defect in circulating dendritic cells in SzS patients that may contribute to the pathogenesis of the cytokine disorders and to the depressed cellular immunity. Importantly, the ability of rCD40L to potently induce IL-12 production from monocytes and residual dendritic cells of SzS patients could potentially serve as an immune-restorative therapeutic agent.

Antigen Presentation↗