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The nucleolar channel system which belongs to less known nuclear components has been described in nerve cells of dog dorsal root ganglia. This structure is formed by a system of twisted tubules. Till now this structure was not observed in all mammalian cells.
Myogenesis is determined by a set of myogenic differentiation factors that are, in turn, regulated by a number of peptide growth factors. During embryonic mouse tongue formation, transforming growth factor alpha (TGF alpha), epidermal growth factor (EGF), and their cognate receptor (EGFR) are co-expressed spatially and temporally with desmin, a muscle-specific structural protein. This investigation tested the hypothesis that TGF alpha directly regulates the myogenic program in developing tongue myoblasts. Mandibular processes from the first branchial arch of embryonic day 10.5 (E10.5) mouse embryos were microdissected and explanted into an organ culture system using serumless chemically defined medium. Exogenous TGF alpha at 10 and 20 ng/ml specifically increased the amount of desmin expression and the number of desmin-positive cells without affecting the general growth and development of the mandibles. This inductive response was detected as early as 2 days after treatment and sustained up to 9 days in culture. EGFR antisense oligonucleotides (30 microM) as well as tyrphostin (80 microM) were able to negate TGF alpha-induced up-regulation of desmin expression. These data indicate that autocrine and/or paracrine action of TGF alpha promotes tongue myogenesis, and that this action is mediated through functional kinase activity of the EGFR. We speculate that the myogenic program in the developing mouse tongue is dependent upon growth factor mediated cell-cell communication of mesenchymal cells originating from the occipital somites and ectomesenchymal cells originating from the cranial neural crest.
In studies of cell adhesion, migration, growth, differentiation, and apoptosis, synthetic peptides containing the RGD (Arg-Gly-Asp) motif have been extensively used as the inhibitors of integrin-ligand interactions. The RGD motif is an integrin-recognition motif found in many ligands, so that the RGD-containing peptides can be used to probe integrin functions in various biological systems. A linear RGD is a tripeptide consisting of a flexible structure that makes the motif bind to its receptor with inefficient chelating affinity. Therefore, we designed a cyclic-RGD peptide (Tpa-RGDWPC, cRGD) with rigid skeleton to closely bind with its receptor. The cRGD was obtained by solid-phase peptide synthesis method using Rink amide resin. We showed that the cRGD exerts more potency than linear RGD on inhibiting cell growth of MCF-7 breast carcinoma cells. This stimulated us to question how cRGD inhibits cell growth of MCF-7 cells. Moreover, understanding what molecular mechanism underlies the effect that RGD motif exerts on MCF-7 cells is also of considerable importance. We used proteomics and bioinformatics to survey the global changes in proteins after cRGD treatment in MCF-7 cells. The classification of these proteins is shown according to the different biological processes in which they are involved. Most of the proteins that appear to be strongly influenced by cRGD treatment are involved in metabolism, cell growth, responsive to external stimulus, cell communication, reproduction and cell death. This is the first report which monitors the protein expression profile of MCF-7 cells in response to treatment with RGD-containing peptides in a time-course analysis. The clustering data indicated temporal patterns of altered protein expression that can be categorized into early, intermediate and late response proteins. These patterns of protein expression may be important for predicting its response to cRGD. In summary, these results provide a molecular explanation for the properties of cRGD in breast cancer cells and present a valuable in-depth description of their possible impact on breast cancer therapy.
Sialic acids play important roles in biological processes, such as cell-cell communication and cell-matrix interaction. Histochemical analysis using PNA and LFA lectin has shown that the expression of alpha 2,3-sialic acid linked to Gal beta 1,3GalNAc is high in basal cells and decreases following further keratinocyte differentiation. In the present study, we used an in vitro keratinocyte cell line differentiation model to study expression of alpha 2,3-sialic acid linked to Gal beta 1,3 GalNAc. Treatment of the human papillomavirus type 16-immortalized human keratinocyte (PHK16) cell line with high concentrations (1.0 mM) of Ca2+ resulted in PHK16 cell differentiation and redistribution of PNA binding glycoproteins. The synthesis of alpha 2,3-sialic acid linked to Gal beta 1,3GalNAc is mediated by three beta-galactoside alpha 2,3-sialytransferases, which are the gene products of hST30, hST30/N and hST3 Gal II. Ca2+ treatment of PHK16 cells decreased the mRNA expression of hST30/N, whereas the mRNA of hST30 and hST3Gal II was not detected by Northern blot analysis, suggesting that the hST30/N gene is responsible for sialic acid down regulation during keratinocyte differentiation. In order to examine transcriptional regulation of the hST30/N gene, we first determined the transcriptional starting sites of the hST30/N gene in PHK 16 using 5'-RACE analysis. Two kinds of type B isoforms, types B3 and BX, were identified. Type BX is a novel isoform related to the type B form, but which differs upstream of the B3 exon. The results of Northern blot analysis using a type BX-specific probe suggest that the B3 promoter may be regulated by Ca2+. Using a luciferase assay, we identified a functional DNA portion within hST30/N genomic DNA that confers negative transcriptional regulation on the hST30/N B3 promoter during Ca2+ stimulated human keratinocyte differentiation. This element contains some putative transcriptional factor binding sequence motifs such as AP2.
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The Hedgehog family of growth factors activate a highly conserved signaling system for cell-cell communication that regulates cell proliferation and differentiation during development. Abnormal activation of the Hedgehog pathway has been demonstrated in a variety of human tumors, including those of the skin, brain, lung and digestive tract. Hedgehog pathway activity in these tumors is required for cancer cell proliferation and tumor growth. Recent studies have uncovered the role for Hedgehog signaling in advanced prostate cancer and demonstrated that autocrine signaling by tumor cells is required for proliferation, viability, and invasive behavior. The level of Hedgehog activity correlates with the severity of the tumor and is both necessary and sufficient for metastatic behavior. Blockade of Hedgehog signaling leads to tumor shrinkage and remission in preclinical tumor xenograft models. Thus, Hedgehog signaling represents a novel pathway in prostate cancer that offers opportunities for prognostic biomarker development, drug targeting and therapeutic response monitoring.
Ischemia is a major stimulus for angiogenesis, a biological response mechanism that describes the formation of new blood vessels from existing vessels. An ischemic cell communicates with endothelial cells by soluble factors such as VEGF (vascular endothelial growth factor) and its receptors. A major transcriptional factor for VEGF is HIF-1 (hypoxia inducible factor). Proliferation of endothelial cells alone does not result in stable vascular tubes, this is only achieved by recruiting additional cells such as pericytes. The stabilisation and destabilisation of vessels, which are important prerequisites for vascular growth, are in a dynamic equilibrium which can be modified by additional growth factors such as angiopoietins. In this review we discuss some of the molecular mechanisms leading from ischemia to proliferative retinopathy with a special focus on retinopathy of prematurity and the closely related mouse model of hyperoxia-induced retinopathy. This model is very useful when developing new antiangiogenic therapies based on the increasing understanding of the molecular pathogenesis of ischemic proliferative retinopathy.
Glomus cells of rat carotid bodies can be electrotonically coupled. This was determined by simultaneous intracellular recording and stimulation of two neighboring cells. Voltage applied into one cell (V1), was detected in the other cell as E2. The ratio E2/V1 or coupling coefficient (KC), varied from 0.003 to 1. R0 or input resistance (24.1-3,500 M omega), was calculated from the voltage elicited in the injected cell by current injection (V1/I1). The coupling resistance (RC) was estimated by using Bennett's model and was inversely related to KC. It ranged from 8.5 to 46,112 M omega. Values for KC are provisional since we may not have always recorded from immediately adjacent cells. Similarly, calculations of R0 and RC may not be accurate since, in all probability, there is a multicellular network. Stimulation by hypoxia (100% N2 or Na2S2O4), acidity (lactic acid or 100% CO2), dopamine, ACh, nicotine and bethanechol depolarized the majority of glomus cells, their input resistance decreased and cells became uncoupled. Fewer cells were either unaffected or coupling increased. There was a significant and negative correlation between changes in coupling coefficient and in coupling resistance.
Cell-cell communication directs the development of photoreceptor cells in the Drosophila retina. A recent set of studies has provided a genetic dissection of one of these interactions, the induction of the R7 photoreceptor cell by the neighboring R8 photoreceptor cell. The results from these experiments shape our understanding of both the molecular basis of signal transduction mediated through receptor tyrosine kinases, as well as the developmental strategies used to generate different cell types in neuronal systems.
Micropatterned cellular co-cultures were fabricated using three major extracellular matrix components: hyaluronic acid (HA), fibronectin (FN) and collagen. To fabricate co-cultures with these components, HA was micropatterned on a glass substrate by capillary force lithography, and the regions of exposed glass were coated with FN to generate cell adhesive islands. Once the first cell type was immobilized on the adhesive islands, the subsequent electrostatic adsorption of collagen to HA patterns switched the non-adherent HA surfaces to adherent, thereby facilitating the adhesion of a second cell type. This technique utilized native extracellular matrix components and therefore affords high biological affinity and no cytotoxicity. This biocompatible co-culture system could potentially provide a new tool to study cell behavior such as cell-cell communication and cell-matrix interactions, as well as tissue-engineering applications.
Cells communicate with other cells via (trans) interaction between membrane-linked ephrins and Eph receptors. In this issue of Cell, Pfaff and colleagues (Marquardt et al., 2005) demonstrate that coexpressed ephrin-As and Ephs do not interact in cis but rather segregate into separate membrane domains, from which they signal opposing effects during motor axon guidance.
During plant epidermal differentiation, root hairs and leaf hairs (trichomes) become specified in a regular pattern. Although the underlying mechanisms appear to be different in that the position of root hairs is determined by their position with respect to the underlying cortical cells and that of the trichomes appears to be generated de novo, a common set of genes was found to operate in both systems. A complex of transcription factors appears to be involved in creating the pattern and cell-cell movement of small transcription factors is postulated to mediate cell-cell communication.
A byproduct of drinking water disinfection, bromochloroacetic acid (BCA), acts as a reproductive toxicant in rats. To determine if BCA produces similar reproductive toxicity in mice, juvenile and adult C57BL/6 males were exposed to 0, 8, 24, 72 or 216 mg/kg of BCA once daily for 14 days. Five of 12 animals from each dose-group were sacrificed at the end of dosing, and testes, epididymes, and seminal vesicles harvested and weighed. Seven mice from each dose-group (including juvenile-exposed mice, following a 14-week maturation period) were used in a 40-day sequential breeding assay to determine if BCA targets a particular phase of spermatogenesis. No significant effects were observed in mice exposed to BCA as juveniles, and there were no effects on fertility by 14 weeks after dosing. However, effects were observed in adult-exposed mice over the first 10 days after BCA exposure: mean number of litters/male, percentage of litters/female bred, and total number of fetuses/male were all reduced by 72 and 216 mg/kg BCA. These results in adult mice indicate BCA disrupted differentiation of spermatids during dosing and the first 10 days of mating, and are consistent with the spermatid retention and atypical residual bodies observed in animals exposed to 72 and 216 mg/kg BCA. To investigate mechanisms involved, we utilized cDNA microarrays containing 950 testis-expressed genes to profile gene expression from Control and BCA-treated mice. Statistical analyses of microarray results identified 40 well-characterized genes differentially expressed in a dose responsive manner as a result of BCA exposure. Microarray results were supplemented with quantitative real-time PCR and Westerns for several genes and proteins. The 40 genes whose expression was altered by BCA are involved in numerous biological processes including: cell communication and adhesion, cell cycle and cell proliferation, metabolism, signal transduction, stress response, and spermatogenesis and male fertility. Modulated expression of these genes, particularly the 15 expressed in Sertoli cells and spermatids, offers new insights into potential mechanisms of BCA toxicity in the mouse testis.
Cell-cell adhesion is a complex process that is involved in the tethering of cells, cell-cell communication, tissue formation, cell migration and the development and metastasis of tumors. Given the heterogeneous and complex nature of cell surfaces it has previously proved difficult to characterize individual cell-cell adhesion events. Force spectroscopy, using an atomic force microscope, is capable of resolving such individual cell-cell binding events, but has previously been limited in its application due to insufficient effective pulling distances. Extended pulling range is critical in studying cell-cell interactions due to the potential for large cell deformations. Here we describe an approach to such experiments, where the sample stage can be moved 100 microm in the z-direction, by closed loop, linearized piezo elements. Such an approach enables an increase in pulling distance sufficient for the observation of long-distance cell-unbinding events without reducing the imaging capabilities of the atomic force microscope. The atomic force microscope head and the piezo-driven sample stage are installed on an inverted optical microscope fitted with a piezo-driven objective, to allow the monitoring of cell morphology by conventional light microscopy, concomitant with force spectroscopy measurements. We have used the example of the WM115 melanoma cell line binding to human umbilical vein endothelial cells to demonstrate the capabilities of this system and the necessity for such an extended pulling range when quantifying cell-cell adhesion events.
Cadherins are calcium-dependent cell adhesion molecules involved in the regulation of various biological processes such as cell recognition, intercellular communication, cell fate, cell polarity, boundary formation, and morphogenesis. Although previous studies have shown E-cadherin expression during rodent or human odontogenesis, there is no equivalent study available on N-cadherin expression in dental tissues. Here we examined and compared the expression patterns of E- and N-cadherins in both embryonic and adult (healthy, injured, carious) human teeth. Both proteins were expressed in the developing teeth during the cap and bell stages. E-cadherin expression in dental epithelium followed an apical-coronal gradient that was opposite to that observed for N-cadherin. E-cadherin was distributed in proliferating cells of the inner and outer enamel epithelia but not in differentiated cells such as ameloblasts, whereas N-cadherin expression was up-regulated in differentiated epithelial cells. By contrast to E-cadherin, N-cadherin was also expressed in mesenchymal cells that differentiate into odontoblasts and produce the hard tissue matrix of dentin. Although N-cadherin was not detected in permanent intact teeth, it was re-expressed during dentin repair processes in odontoblasts surrounding carious or traumatic sites. Similarly, N-cadherin re-expression was seen in vitro, in cultured primary pulp cells that differentiate into odontoblast-like cells. Taken together these results suggest that E- and N-cadherins may play a role during human tooth development and, moreover, indicate that N-cadherin is important for odontoblast function in normal development and under pathological conditions.
Neurons in most peripheral ganglia are surrounded by satellite glial cells (SCs), but these cells have so far received little attention. We used immunohistochemistry and intracellular injections of tracers to characterize SCs in the intramural ganglia of the guinea-pig urinary bladder, which are part of the parasympathetic system. Intracellular injections of horseradish peroxidase (HRP) revealed two morphological types: cells that surrounded neurons and are SCs proper, and bipolar cells with processes that projected into the nerve fiber bundles connecting the ganglia. SCs were immunopositive for glutamine synthetase (GS) and S100beta and immunonegative for glial fibrillary acidic protein (GFAP). Injections of Lucifer yellow (LY) or biocytin (molecules known to cross gap junctions) into single SCs showed that these cells have a very low degree of intercellular coupling. A mean of 0.31 and 0.71 cells were coupled to the injected cells, using LY and biocytin, respectively. It appears that SCs in the bladder ganglia are distinct from central and enteric glial cells in the small degree of their coupling and in the absence of GFAP immunostaining.
The distributions of Merkel cells and Langerhans cells within human hair follicles have been reported. However, there has been no description of the relationship between Merkel cells and Langerhans cells, which were discovered by 19th century German pathologists. Merkel cells and Langerhans cells share some similar characteristics such as the localization of human hair follicles, a close association with peripheral nerves and the expression of several neuropeptides. Merkel cells were stained with CK20 or CAM5.2, while Langerhans cells were stained with CD1a or S-100 protein. We thus immunohistochemically confirmed the preferential localization of Merkel cells and Langerhans cells in normal human hair follicles. Using a double staining technique, two- and three-dimensional observations demonstrated that a small proportion of Merkel cells were closely contacted with Langerhans cells below the sebaceous gland level, presumably indicating the bulge area. Merkel cells and Langerhans cells connected directly or approached each dendrite within the basal layer of the outer root sheath. For the first time, we demonstrated a close anatomical relationship between Merkel cells and Langerhans cells within the bulge area of human hair follicles where follicular stem cells may be present. These morphological observations suggest a functional interaction between follicular Merkel cells and Langerhans cells. We herein hypothesize that Merkel cells communicate with Langerhans cells by characteristic dendrites in which some neuropeptides or cytokines may be stored.
BACKGROUND: T cells and B cells communicate by direct cell--cell interaction that is crucial to the functioning of the immune system. It is well established that the interaction between B-cell-expressed CD40 and T-cell-expressed CD40 ligand (CD40L) is critical for T-cell-dependent antibody responses, but the role of this interaction in T-cell responses is less clear. In this study, we have used mice with targeted mutations in the genes encoding CD40L or CD28 to investigate how the CD40-CD40L interaction induces on B cells a costimulatory activity that acts in addition to antigen to trigger T-cell growth. RESULTS: We show that T cells from Cd40L-deficient mice induce a substantially reduced costimulatory activity on B cells compared to wild-type T cells, particularly at early time points. Surprisingly, T cells, from CD40L-deficient mice induce similar levels of B7-1 and B7-2 as do wild-type T cells. We further show that the CD40L-mediated induction of costimulatory activity precedes the induction of B7-1, B7-2 and the heat-stable antigen (HSA). CD4 T cells isolated from the CD28-deficient mice can receive costimulatory activity from CD40L-induced B cells, demonstrating that the induced molecules can costimulate T cells by a CD28-independent mechanism. We have generated a novel monoclonal antibody that inhibits the CD40L-induced costimulatory activity. Expression of the epitope detected by this monoclonal antibody correlates with the induction of the costimulatory activity, and the molecule recognized by the monoclonal antibody is a single chain of around 85 kDa, distinct from B7-1, B7-2, ICAM-1, ICAM-2, ICAM-3, HSA CD5, integrin and 4-1BB ligand. CONCLUSIONS: Our results demonstrate that CD40L is both necessary and sufficient for rapid, T-cell-mediated induction of costimulatory activity on B cells. This costimulatory activity is distinct from B7-1 and B7-2, and is independent of CD28.