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Synapses are the basic units for information processing and storage in the nervous system. It is only when the synaptic connection is established, that it becomes meaningful to discuss the structure and function of a circuit. In humans, our unparalleled cognitive abilities are correlated with an increase in the number of synapses. Additionally, genes involved in synaptogenesis are also frequently associated with neurological or psychiatric disorders, suggesting a relationship between synaptogenesis and brain physiology and pathology. Thus, understanding the molecular mechanisms of synaptogenesis is the key to the mystery of circuit assembly and neural computation. Furthermore, it would provide therapeutic insights for the treatment of neurological and psychiatric disorders. Multiple molecular events must be precisely coordinated to generate a synapse. To understand the molecular mechanisms underlying synaptogenesis, we need to know the molecular components of synapses, how these molecular components are held together, and how the molecular networks are refined in response to neural activity to generate new synapses. Thanks to the intensive investigations in this field, our understanding of the process of synaptogenesis has progressed significantly. Here, we will review the molecular mechanisms of synaptogenesis by going over the studies on the identification of molecular components in synapses and their functions in synaptogenesis, how cell adhesion molecules connect these synaptic molecules together, and how neural activity mobilizes these molecules to generate new synapses. Finally, we will summarize the human-specific regulatory mechanisms in synaptogenesis and results from human genetics studies on synaptogenesis and brain disorders.

The obligate intracellular parasite Toxoplasma gondii makes use of infected leukocytes for systemic dissemination. Yet, how infection impacts the processes of leukocyte diapedesis has remained unresolved. Here, we addressed the effects of T. gondii infection on the trans-endothelial migration (TEM) of dendritic cells (DCs) across polarised brain endothelial monolayers. We report that upregulated expression of leukocyte ICAM-1 is a feature of the enhanced TEM of parasitised DCs. The secreted parasite effector GRA15 induced an elevated expression of ICAM-1 in infected DCs that was associated with enhanced cell adhesion and TEM. Consequently, gene silencing of Icam-1 in primary DCs or deletion of parasite GRA15 reduced TEM. Further, the parasite effector TgWIP, which impacts the regulation of host actin dynamics, facilitated TEM across polarised endothelium. The data highlight that the concerted action of the secreted effectors GRA15 and TgWIP modulate the leukocyte-endothelial interactions of TEM in a parasite genotype-related fashion to promote dissemination. In addition to the canonical roles of endothelial ICAM-1, this study identifies a previously unappreciated role for leukocyte ICAM-1 in infection-related TEM. [ABSTRACT FROM AUTHOR]

The β2 subunit of Na+, K+-ATPase was originally identified as the adhesion molecule on glia (AMOG) that mediates the adhesion of astrocytes to neurons in the central nervous system and that is implicated in the regulation of neurite outgrowth and neuronal migration. While β1 isoform have been shown to trans-interact in a species-specific mode with the β1 subunit on the epithelial neighboring cell, the β2 subunit has been shown to act as a recognition molecule on the glia. Nevertheless, none of the works have identified the binding partner of β2 or described its adhesion mechanism. Until now, the interactions pronounced for β2/AMOG are heterophilic cis-interactions. In the present report we designed experiments that would clarify whether β2 is a cell–cell homophilic adhesion molecule. For this purpose, we performed protein docking analysis, cell–cell aggregation, and protein–protein interaction assays. We observed that the glycosylated extracellular domain of β2/AMOG can make an energetically stable trans-interacting dimer. We show that CHO (Chinese Hamster Ovary) fibroblasts transfected with the human β2 subunit become more adhesive and make large aggregates. The treatment with Tunicamycin in vivo reduced cell aggregation, suggesting the participation of N-glycans in that process. Protein–protein interaction assay in vivo with MDCK (Madin-Darby canine kidney) or CHO cells expressing a recombinant β2 subunit show that the β2 subunits on the cell surface of the transfected cell lines interact with each other. Overall, our results suggest that the human β2 subunit can form trans-dimers between neighboring cells when expressed in non-astrocytic cells, such as fibroblasts (CHO) and epithelial cells (MDCK). [ABSTRACT FROM AUTHOR]

The obligate intracellular parasite Toxoplasma gondii makes use of infected leukocytes for systemic dissemination. Yet, how infection impacts the processes of leukocyte diapedesis has remained unresolved. Here, we addressed the effects of T. gondii infection on the trans-endothelial migration (TEM) of dendritic cells (DCs) across polarised brain endothelial monolayers. We report that upregulated expression of leukocyte ICAM-1 is a feature of the enhanced TEM of parasitised DCs. The secreted parasite effector GRA15 induced an elevated expression of ICAM-1 in infected DCs that was associated with enhanced cell adhesion and TEM. Consequently, gene silencing of Icam-1 in primary DCs or deletion of parasite GRA15 reduced TEM. Further, the parasite effector TgWIP, which impacts the regulation of host actin dynamics, facilitated TEM across polarised endothelium. The data highlight that the concerted action of the secreted effectors GRA15 and TgWIP modulate the leukocyte-endothelial interactions of TEM in a parasite genotype-related fashion to promote dissemination. In addition to the canonical roles of endothelial ICAM-1, this study identifies a previously unappreciated role for leukocyte ICAM-1 in infection-related TEM.

Alzheimer’s disease (AD) is an incurable neurodegenerative disorder in which dysfunction and loss of synapses and neurons lead to cognitive impairment and death. Accumulation and aggregation of neurotoxic amyloid-β (Aβ) peptides generated via amyloidogenic processing of amyloid precursor protein (APP) is considered to play a central role in the disease etiology. APP interacts with cell adhesion molecules, which influence the normal physiological functions of APP, its amyloidogenic and non-amyloidogenic processing, and formation of Aβ aggregates. These cell surface glycoproteins also mediate attachment of Aβ to the neuronal cell surface and induce intracellular signaling contributing to Aβ toxicity. In this review, we discuss the current knowledge surrounding the interactions of cell adhesion molecules with APP and Aβ and analyze the evidence of the critical role these proteins play in regulating the processing and physiological function of APP as well as Aβ toxicity. This is a necessary piece of the complex AD puzzle, which we should understand in order to develop safe and effective therapeutic interventions for AD.

Alcohol exposure during pregnancy disrupts the development of the brain and produces long lasting behavioral and cognitive impairments collectively known as Fetal Alcohol Spectrum Disorders (FASDs). FASDs are characterized by alterations in learning, working memory, social behavior and executive function. A large body of literature using preclinical prenatal alcohol exposure models reports alcohol-induced changes in architecture and activity in specific brain regions affecting cognition. While multiple putative mechanisms of alcohol's long-lasting effects on morphology and behavior have been investigated, an area that has received less attention is the effect of alcohol on cell adhesion molecules (CAMs). The embryo/fetal development represents a crucial period for Central Nervous System (CNS) development during which the cell-cell interaction plays an important role. CAMs play a critical role in neuronal migration and differentiation, synaptic organization and function which may be disrupted by alcohol. In this review, we summarize the physiological structure and role of CAMs involved in brain development, review the current literature on prenatal alcohol exposure effects on CAM function in different experimental models and pinpoint areas needed for future study to better understand how CAMs may mediate the morphological, sensory and behavioral outcomes in FASDs. [ABSTRACT FROM AUTHOR]

Alcohol exposure during pregnancy disrupts the development of the brain and produces long lasting behavioral and cognitive impairments collectively known as Fetal Alcohol Spectrum Disorders (FASDs). FASDs are characterized by alterations in learning, working memory, social behavior and executive function. A large body of literature using preclinical prenatal alcohol exposure models reports alcohol-induced changes in architecture and activity in specific brain regions affecting cognition. While multiple putative mechanisms of alcohol’s long-lasting effects on morphology and behavior have been investigated, an area that has received less attention is the effect of alcohol on cell adhesion molecules (CAMs). The embryo/fetal development represents a crucial period for Central Nervous System (CNS) development during which the cell-cell interaction plays an important role. CAMs play a critical role in neuronal migration and differentiation, synaptic organization and function which may be disrupted by alcohol. In this review, we summarize the physiological structure and role of CAMs involved in brain development, review the current literature on prenatal alcohol exposure effects on CAM function in different experimental models and pinpoint areas needed for future study to better understand how CAMs may mediate the morphological, sensory and behavioral outcomes in FASDs.

The β2 subunit of Na+, K+-ATPase was originally identified as the adhesion molecule on glia (AMOG) that mediates the adhesion of astrocytes to neurons in the central nervous system and that is implicated in the regulation of neurite outgrowth and neuronal migration. While β1 isoform have been shown to trans-interact in a species-specific mode with the β1 subunit on the epithelial neighboring cell, the β2 subunit has been shown to act as a recognition molecule on the glia. Nevertheless, none of the works have identified the binding partner of β2 or described its adhesion mechanism. Until now, the interactions pronounced for β2/AMOG are heterophilic cis-interactions. In the present report we designed experiments that would clarify whether β2 is a cell–cell homophilic adhesion molecule. For this purpose, we performed protein docking analysis, cell–cell aggregation, and protein–protein interaction assays. We observed that the glycosylated extracellular domain of β2/AMOG can make an energetically stable trans-interacting dimer. We show that CHO (Chinese Hamster Ovary) fibroblasts transfected with the human β2 subunit become more adhesive and make large aggregates. The treatment with Tunicamycin in vivo reduced cell aggregation, suggesting the participation of N-glycans in that process. Protein–protein interaction assay in vivo with MDCK (Madin-Darby canine kidney) or CHO cells expressing a recombinant β2 subunit show that the β2 subunits on the cell surface of the transfected cell lines interact with each other. Overall, our results suggest that the human β2 subunit can form trans-dimers between neighboring cells when expressed in non-astrocytic cells, such as fibroblasts (CHO) and epithelial cells (MDCK).

Pulmonary inflammation and tissue remodelling are common elements of chronic respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and pulmonary hypertension (PH). In disease, pulmonary mesenchymal cells not only contribute to tissue remodelling, but also have an important role in pulmonary inflammation. This review will describe the immunomodulatory functions of pulmonary mesenchymal cells, such as airway smooth muscle (ASM) cells and lung fibroblasts, in chronic respiratory disease. An important theme of the review is that pulmonary mesenchymal cells not only respond to inflammatory mediators, but also produce their own mediators, whether pro-inflammatory or pro-resolving, which influence the quantity and quality of the lung immune response. The notion that defective pro-inflammatory or pro-resolving signalling in these cells potentially contributes to disease progression is also discussed. Finally, the concept of specifically targeting pulmonary mesenchymal cell immunomodulatory function to improve therapeutic control of chronic respiratory disease is considered. [ABSTRACT FROM AUTHOR]

Abstract: Cells respond to their environment in complex and sometimes poorly understood ways. Protein, peptide and synthetic peptidomimetic ligands may all be used to stimulate cells via receptor signaling, using interactions that are often highly specific. Polymer substrates that present these ligands provide a promising way to control cell development, both for applications in biotechnology and for fundamental studies of cell biology. Here we review a large range of techniques that have been employed to create and characterize ligand-functionalized substrates, with a particular focus on techniques that allow specific and consistent stimulation. [Copyright &y& Elsevier]

Over the last few years, the field of microribonucleic acid (miRNA) in cardiovascular biology and disease has expanded at an incredible pace. miRNAs are themselves part of a larger family, that of non-coding RNAs, the importance of which for biological processes is starting to emerge. miRNAs are ∼22-nucleotide-long RNA sequences that can legate messenger (m)RNAs at partially complementary binding sites, and hence regulate the rate of protein synthesis by altering the stability of the targeted mRNAs. In the cardiovascular system, miRNAs have been shown to be critical regulators of development and physiology. They control basic functions in virtually all cell types relevant to the cardiovascular system (such as endothelial cells, cardiac muscle, smooth muscle, inflammatory cells, and fibroblasts) and, thus, are directly involved in the pathophysiology of many cardiovascular diseases. As a result of their role in disease, they are being studied for exploitation in diagnostics, prognostics, and therapeutics. However, there are still significant obstacles that need to be overcome before they enter the clinical arena. We present here a review of the literature and outline the directions toward their use in the clinic. [Copyright &y& Elsevier]

Highlights: [•] OECD 28-day inhalation study: Histopathology was combined with transcriptomics. [•] Histopathological changes correlated with biological network perturbation. [•] Tissue-specific impact on network perturbation was quantified. [•] Reduced biological activity of a MRTP compared to 3R4F was demonstrated. [•] Network-based approach facilitates systems toxicology-based risk assessment. [ABSTRACT FROM AUTHOR]

Abstract: In the review article presented here, we demonstrate that the connective tissue is more than just a matrix for cells and a passive scaffold to provide physical support. The extracellular matrix can be subdivided into proteins (collagen, elastin), glycoconjugates (structural glycoproteins, proteoglycans) and glycosaminoglycans (hyaluronan). Our main focus rests on the anionic biopolyelectrolytes of the perlecan/syndecan superfamily which belongs to extracellular matrix and cell membrane integral proteoglycans. Though the extracellular domain of the syndecans may well be performing a structural role within the extracellular matrix, a key function of this class of membrane intercalated proteoglycans may be to act as signal transducers across the plasma membrane and thus be more appropriately included in the group of cell surface receptors. Nevertheless, there is a continuum in functions of syndecans and perlecans, especially with respect to their structural role and biomedical significance. HS/CS proteoglycans are receptor sites for lipoprotein binding thus intervening directly in lipid metabolism. We could show that among all lipoproteins, HDL has the highest affinity to these proteoglycans and thus instals a feedforward forechecking loop against atherogenic apoB100 lipoprotein deposition on surface membranes and in subendothelial spaces. Therefore, HDL is not only responsible for VLDL/IDL/LDL cholesterol exit but also controls thoroughly the entry. This way, it inhibits arteriosclerotic nanoplaque formation. The ternary complex ‘lipoprotein receptor (HS/CS-PG) – lipoprotein (LDL, oxLDL, Lp(a)) – calcium’ may be interpreted as arteriosclerotic nanoplaque build-up on the molecular level before any cellular reactivity, possibly representing the arteriosclerotic primary lesion combined with endothelial dysfunction. With laser-based ellipsometry we could demonstrate that nanoplaque formation is a Ca2+-driven process. In an in vitro biosensor application of HS-PG coated silica surfaces we tested nanoplaque formation and size in clinical trials with cardiovascular high-risk patients who underwent treatment with ginkgo or fluvastatin. While ginkgo reduced nanoplaque formation (size) by 14.3% (23.4%) in the isolated apoB100 lipid fraction at a normal blood Ca2+ concentration, the effect of the statin with a reduction of 44.1% (25.4%) was more pronounced. In addition, ginkgo showed beneficial effects on several biomarkers of oxidative stress and inflammation. Besides acting as peripheral lipoprotein binding receptor, HS/CS-PG is crucially implicated in blood flow sensing. A sensor molecule has to fulfil certain mechanochemical and mechanoelectrical requirements. It should possess viscoelastic and cation binding properties capable of undergoing conformational changes caused both mechanically and electrostatically. Moreover, the latter should be ion-specific. Under no-flow conditions, the viscoelastic polyelectrolyte at the endothelium — blood interface assumes a random coil form. Blood flow causes a conformational change from the random coil state to the directed filament structure state. This conformational transition effects a protein unfurling and molecular elongation of the GAG side chains like in a ‘stretched’ spring. This configuration is therefore combined with an increase in binding sites for Na+ ions. Counterion migration of Na+ along the polysaccharide chain is followed by transmembrane Na+ influx into the endothelial cell and by endothelial cell membrane depolarization. The simultaneous Ca2+ influx releases NO and PGI2, vasodilatation is the consequence. Decrease in flow reverses the process. Binding of Ca2+ and/or apoB100 lipoproteins (nanoplaque formation) impairs the flow sensor function. The physicochemical and functional properties of proteoglycans are due to their amphiphilicity and anionic polyelectrolyte character. Thus, they potently interact with cations, albeit in a rather complex manner. Utilizing 23Na+ and 39 K+ NMR techniques, we could show that, both in HS-PG solutions and in native vascular connective tissue, the mode of interaction for monovalent cations is competition. Mg2+ and Ca2+ ions, however, induced a conformational change leading to an increased allosteric, cooperative K+ and Na+ binding, respectively. Since extracellular matrices and basement membranes form a tight-fitting sheath around the cell membrane of muscle and Schwann cells, in particular around sinus node cells of the heart, and underlie all epithelial and endothelial cell sheets and tubes, a release of cations from or an adsorption to these polyanionic macromolecules can transiently lead to fast and drastic activity changes in these tiny extracellular tissue compartments. The ionic currents underlying pacemaker and action potential of sinus node cells are fundamentally modulated. Therefore, these polyelectrolytic ion binding characteristics directly contribute to and intervene into heart rhythm. [Copyright &y& Elsevier]

Abstract: Axonal injury and degeneration, whether primary or secondary, contribute to the morbidity and mortality seen in many acquired and inherited central nervous system (CNS) and peripheral nervous system (PNS) disorders, such as traumatic brain injury, spinal cord injury, cerebral ischemia, neurodegenerative diseases, and peripheral neuropathies. The calpain family of proteases has been mechanistically linked to the dysfunction and degeneration of axons. While the direct mechanisms by which transection, mechanical strain, ischemia, or complement activation trigger intra-axonal calpain activity are likely different, the downstream effects of unregulated calpain activity may be similar in seemingly disparate diseases. In this review, a brief examination of axonal structure is followed by a focused overview of the calpain family. Finally, the mechanisms by which calpains may disrupt the axonal cytoskeleton, transport, and specialized domains (axon initial segment, nodes, and terminals) are discussed. [Copyright &y& Elsevier]

Highlights: [•] Ectopically expressed FERM is largely located in the cytosolic fraction. [•] FERM promotes apoptosis induced by resveratrol at high dose, but not by TNF-α. [•] NO and eNOS activity are prompted by resveratrol, but not by TNF-α. [•] Cytosolic FERM diminishes eNOS phosphorylation and NO level. [•] An NO donor reverses FERM/resveratrol-induced apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: Reversible tyrosine phosphorylation of proteins is a key regulatory mechanism to steer normal development and physiological functioning of multicellular organisms. Phosphotyrosine dephosphorylation is exerted by members of the super-family of protein tyrosine phosphatase (PTP) enzymes and many play such essential roles that a wide variety of hereditary disorders and disease susceptibilities in man are caused by PTP alleles. More than two decades of PTP research has resulted in a collection of PTP genetic variants with corresponding consequences at the molecular, cellular and physiological level. Here we present a comprehensive overview of these PTP gene variants that have been linked to disease states in man. Although the findings have direct bearing for disease diagnostics and for research on disease etiology, more work is necessary to translate this into therapies that alleviate the burden of these hereditary disorders and disease susceptibilities in man. [Copyright &y& Elsevier]

Highlights: [•] The expression pattern of Lrrn4 was investigated in the DRGs during development. [•] We used Lrrn4 reporter knock-in mice to characterize Lrrn4-expressing cells. [•] The expression of Lrrn4 was dynamically changed in developing DRG neurons. [•] The expression of Lrrn4 may correlate to the synaptogenesis in the spinal cord. [ABSTRACT FROM AUTHOR]

Highlights: [•] Transcript and protein of rKirre are increased in postnatal cerebellar development. [•] rKirre mRNA is expressed in migrating granule cells and developing Purkinje cells. [•] rKirre protein is co-localized with a neuron marker NF-200 in Purkinje cells. [•] rKirre may contribute to the granule cell migration and Purkinje cell development. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Piper longum L. fruits have been traditionally used against snakebites in north-eastern and southern region of India. Aim of the study: To examine the ability of ethanolic extract of fruits of Piper longum L., Piperaceae (PLE) and piperine, one of the main active principles of Piper longum, to inhibit the Russell's viper (Doboia russelii, Viperidae) snake venom activities. Materials and methods: Anti-snake venom activities of ethanolic extract of fruits of Piper longum L. (Piperaceae) and piperine against Russell's viper venom was studied in embryonated fertile chicken eggs, mice and rats by using various models as follows: inhibition of venom lethal action, inhibition of venom haemorrhagic action (in vitro), inhibition of venom haemorrhagic action (in vivo), inhibition of venom necrotizing action, inhibition of venom defibrinogenating action, inhibition of venom induced paw edema, inhibition of venom induced mast cell degranulation, creatine kinase assay and assay for catalase activity. Results: PLE was found to inhibit the venom induced haemorrhage in embryonated fertile chicken eggs. Administration of PLE and piperine significantly (p<0.01) inhibited venom induced lethality, haemorrhage, necrosis, defibrinogenation and inflammatory paw edema in mice in a dose dependent manner. PLE and piperine also significantly (p<0.01) reduced venom induced mast cell degranulation in rats. Venom induced decrease in catalase enzyme levels in mice kidney tissue and increase in creatine kinase enzyme levels in mice serum were significantly (p<0.01) reversed by administration of both PLE and piperine. Conclusions: PLE possesses good anti-snake venom properties and piperine is one of the compounds responsible for the effective venom neutralizing ability of the plant. [Copyright &y& Elsevier]

To identify the genes that determine differentiation phenotypes, we compared gene expression of pancreatic islet β- and α-cells, which are derived from the common precursor and secrete insulin and glucagon, respectively. The expression levels of homeotic genes including Hox genes known to determine region specificity in the antero-posterior (AP) body axis, tissue-specific homeobox genes, and other 8,734 genes were compared in a β- and α-cell line of MIN6 and αTC1.6. The expression of homeotic genes were surveyed with reverse transcription-polymerase chain reaction (RT-PCR) using degenerate primers corresponding to invariant amino acid sequences within the homeodomain and subsequently with specific primers. Expression of Hoxc6, Hoxc9, Hoxc10, Pdx1, Cdx2, Gbx2, Pax4, and Hlxb9 genes in MIN6 was higher than those in αTC1.6, while expression of Hoxa2, Hoxa3, Hoxa5, Hoxa6, Hoxa7, Hoxa9, Hoxa10, Hoxa13, Hoxb3, Hoxb5, Hoxb6, Hoxb13, Hoxb8, and Brain4 genes in αTC1.6 was higher than those in MIN6. Out of 8,734 mouse genes screened with high-density mouse cDNA microarrays for MIN6- and αTC1.6-derived cDNA, 58 and 25 genes were differentially over- and under-expressed in MIN6, respectively. GLUTag, which is derived from a large bowel tumor and expresses the proglucagon gene, showed a comparatively similar expression profile to that of αTC1.6 in both homeotic and other genes analyzed in cDNA microarray.Our results are consistent with the interpretation that not only the tissue-specific homeotic genes, but also Hox genes are related to differentiation phenotypes of pancreatic β- and α-cells rather than their regional specification of the body in vertebrates. [Copyright &y& Elsevier]

MUC18, a cell adhesion molecule (CAM), has been reported to be a diagnostic marker for the early detection of the metastatic potential of prostate cancers as well as implicated to be an important determinant for mediating the tumorigenesis and metastasis of prostate cancer. To test the hypothesis, we further investigated the possible role of MUC18 in the malignant progression of human prostate cancer. The human MUC18-minus, non-metastatic human prostate cancer LNCaP cells were transfected with the human cytomegalovirus immediate-early gene (HCMV-IE) promoter-driven human MUC18 (huMUC18) cDNA. The G418-resistant (G418R)-LNCaP clones that expressed a high level of huMUC18 were selected and used for testing the effect of huMUC18 expression on the in vitro growth, motility, and invasiveness as well as on the in vivo metastasis (via orthotopical injection) in a xenograft nude mouse model. HuMUC18 expression increased by four- to fivefold of in vitro motility and invasiveness of LNCaP cells. Anti-huMUC18 antibody significantly inhibited the in vitro motility and invasiveness of huMUC18-expressing LNCaP clones, but not the control clones. We suggest that huMUC18 expression is responsible for increasing these behaviors of LNCaP cells. HuMUC18 expression also directly increased the in vivo metastatic abilities of the LNCaP cells from the prostate gland to multiple distant organs. Western blot and immunohistochemistry analyses showed that the prostatic tumors as well as metastatic lesions expressed high levels of MUC18, indicating that they originated from the injected huMUC18-expressing LNCaP cells. We therefore conclude that HuMUC18 is an important determinant in increasing metastasis of human prostate cancer LNCaP cells to distant organs in a nude mouse model. [Copyright &y& Elsevier]

Differentiating neurons must acquire many unique morphological and functional characteristics in creating the precise neural circuits of the mature nervous system. The phenomenon of ‘neuronal differentiation’ includes a special set of simple, separate processes, that is, neuritogenesis, neurite outgrowth, pathfinding, targeting and synaptogenesis. All of these processes are critically dependent on the reorganization of actin cytoskeleton by many actin-binding proteins that function downstream of Rho-family GTPases. Furthermore, de novo synthesis of key proteins are critically involved in the reorganization of actin cytoskeleton during neuronal differentiation. In this article, we review recent progresses in the general mechanisms that control actin dynamics by various actin-binding proteins in differentiating neurons, including a series of recent studies from our laboratory on de novo synthesis of several key proteins that are essential for actin reorganization induced by second messengers. We demonstrated that dual regulation of cyclic AMP and Ca2+ determines cofilin (an actin-binding protein) phosphorylation states and LIM kinase 1 (a cofilin kinase) expression level during neuritogenesis. [Copyright &y& Elsevier]

The mouse optic chiasm is a model for axon guidance at the midline and for analyzing how binocular vision is patterned. Recent work has identified several molecular players that influence the binary decision that retinal ganglion cells make at the optic chiasm, to either cross or avoid the midline. An ephrin-B localized to the midline, together with an EphB receptor and a zinc-finger transcription factor expressed exclusively in the ventrotemporal retina where ipsilaterally projecting retinal ganglion cells are located, comprise a molecular program for the uncrossed pathway. In addition, the mechanisms for axon divergence in the optic chiasm are discussed in the context of other popular models for midline axon guidance. [Copyright &y& Elsevier]

The F11 receptor (F11R) (a.k.a. Junctional Adhesion Molecule, JAM) was first identified in human platelets as a 32/35 kDa protein duplex that serves as receptor for a functional monoclonal antibody that activates platelets. We have sequenced and cloned the F11R and determined that it is a member of the immunoglobulin (Ig) superfamily of cell adhesion molecules. The signaling pathways involved in F11R-induced platelet activation were examined in this investigation. The binding of M.Ab.F11 to the platelet F11R resulted in granule secretion and aggregation. These processes were found to be dependent on the crosslinking of F11R with the FcγRII by M.Ab.F11. This crosslinking induced actin filament assembly with the conversion of discoidal platelets to activated shapes, leading to the formation of platelet aggregates. We demonstrate that platelet secretion and aggregation through the F11R involves actin filament assembly that is dependent on phosphoinositide-3 kinase activation, and inhibitable by wortmannin. Furthermore, such activation results in an increase in the level of free intracellular calcium, phosphorylation of the 32 and 35 kDa forms of the F11R, F11R dimerization coincident with a decrease in monomeric F11R, and association of the F11R with the integrin GPIIIa and with CD9. On the other hand, F11R-mediated events resulting from the binding of platelets to an immobilized surface of M.Ab.F11 lead to platelet adhesion and spreading through the development of filopodia and lammelipodia. These adhesive processes are induced directly by interaction of M.Ab.F11 with the platelet F11R and are not dependent on the FcγRII. We also report here that the stimulation of the F11R in the presence of nonaggregating (subthreshold) concentrations of the physiological agonists thrombin and collagen, results in supersensitivity of platelets to natural agonists by a F11R-mediated process independent of the FcγRII. The delineation of the two separate F11R-mediated pathways is anticipated to reveal significant information on the role of this cell adhesion molecule in platelet adhesion, aggregation and secretion, and F11R-dependent potentiation of agonist-induced platelet aggregation. The participation of F11R in the formation and growth of platelet aggregates and plaques in cardiovascular disorders, resulting in enhanced platelet adhesiveness and hyperaggregability, may serve in the generation of novel therapies in the treatment of inflammatory thrombosis, heart attack and stroke, and other cardiovascular disorders. [ABSTRACT FROM AUTHOR]

Opioid-binding cell adhesion molecule (OBCAM) is a member of the immunoglobulin superfamily containing limbic system-associated membrane protein (IgLON) subgroup of glycosylphosphatidylinositol-anchored immunoglobulin cell adhesion molecules. We have previously found that OBCAM is localized preferentially to dendrites compared with somata and terminals of hypothalamic vasopressin-secreting magnocellular neurons. This localization indicates that OBCAM is one of the dendrite-associated cell adhesion molecules. In the present study, we further characterized the localization and the sorting mechanism, and activity-dependent changes of this molecule in vasopressin-secreting magnocellular dendrites. Confocal microscopic observation revealed the preferential localization of OBCAM at the neurosecretory granules in the vasopressin-positive dendrites. Electron microscopic observation using chromogen-intensified and gold-conjugated methods also demonstrated the OBCAM labeling at most of the neurosecretory granules within the dendrites, while the labeling within the somata was observed at only a few neurosecretory granules. I.c.v. colchicine administration resulted in the disappearance of OBCAM immunoreactivity from the dendrites and in its concomitant accumulation at the somata, suggesting that OBCAM is synthesized at the somata and transported to the dendrites by dendrite-associated neurosecretory granules. During the postnatal development, OBCAM immunoreactivity targeted to vasopressin-positive dendrites became clear from at least 3 weeks after birth, although it appeared at only a few somata 2 weeks after birth. Phosphatidylinositol specific phospholipase C treatment of the membrane fraction of the supraoptic homogenate solubilized OBCAM. Kilon, another IgLON member, was also shown to localize at the neurosecretory granules of vasopressin-positive dendrites via the glycosylphosphatidylinositol anchor. High K+-stimulation appeared to cause the diffusion of OBCAM-labeled gold particles from neurosecretory granules together with the exocytosis.These findings indicate that OBCAM is synthesized within the somata, attached to vasopressin neurosecretory granules via the glycosylphosphatidylinositol anchor, and transported to the dendrites. Moreover, the subcellular localization of OBCAM is changed in an activity-dependent manner. [Copyright &y& Elsevier]

: ObjectivesWe sought to assess the effect of rosiglitazone on markers of endothelial cell activation and acute-phase reactants in non-diabetic patients with coronary artery disease (CAD).: BackgroundInflammation plays a key role in all stages of atherosclerosis and in the genesis of acute coronary syndromes. Rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist, is used in the treatment of type 2 diabetes mellitus, and previous data suggest that it may have anti-inflammatory effects on atherosclerosis.: MethodsPatients with stable, angiographically documented CAD without diabetes mellitus were investigated. Patients were randomized in a double-blind manner to receive treatment with placebo or rosiglitazone (4 mg/day for 8 weeks followed by 8 mg/day for 4 weeks) for 12 weeks. Eighty-four patients completed the study. Fasting glucose, insulin, lipid profile, markers of endothelial activation, and inflammatory markers were measured at baseline and after 12 weeks.: ResultsRosiglitazone treatment resulted in a significant reduction in E-selectin (p = 0.03), von Willebrand factor (p = 0.007), C-reactive protein (p < 0.001), fibrinogen (p = 0.003) and the homeostasis model of insulin resistance index (p = 0.02), compared with placebo. Significant elevations in low-density lipoprotein and triglyceride levels were observed in the rosiglitazone group (p < 0.01). Within the rosiglitazone-treated group, reductions in C-reactive protein and von Willebrand factor were significantly correlated with a reduction in insulin resistance.: ConclusionsRosiglitazone significantly reduces markers of endothelial cell activation and levels of acute-phase reactants in CAD patients without diabetes. Potential underlying mechanisms include insulin sensitization and direct modification of transcription within the vessel wall. [Copyright &y& Elsevier]

Axo-glial interactions are required for the organization of highly specialized molecular domains in myelinated axons. The molecular composition of these domains includes cell adhesion molecules, ion channels and cytoskeletal proteins. Recent genetic and molecular studies provide new insights into how these macromolecular complexes are assembled and organized into functional domains, and how the loss of individual components affects domain organization and function. More importantly, the key molecular components identified at the vertebrate axo-glial septate junctions are also present at the Drosophila septate junctions. In addition, new roles for axo-glial paranodal septate junctions have emerged, which suggest that the paranodal region may act as an ionic barrier and a molecular fence in myelinated axons. [Copyright &y& Elsevier]

Cell adhesion molecules of the immunoglobulin superfamily (IgCAMS) play pivotal roles during synapse development and remodeling, being required in both activity-dependent and activity independent aspects of these processes. Recent advances using the fruit fly neuromuscular junction, as well as the mollusk Aplysia californica, have provided evidence for at least three mechanisms by which levels of IgCAMs are regulated during synapse remodeling — activity-dependent regulation of IgCAM clustering by PSD-95-type molecules, IgCAM internalization by MAP kinase pathway activation, and postsynaptic IgCAM exocytosis. These studies offer convincing evidence that synaptic cell adhesion brings about both negative and positive forces that stabilize synapses, while maintaining their ability to change in an activity-dependent manner. [Copyright &y& Elsevier]

Cell adhesion molecules, such as integrins, cadherins, the immunoglobulin superfamily of cell adhesion molecules and selectins, play important structural roles and are involved in various signal transduction processes. As an initial step in the infectious process, many bacterial pathogens adhere to cell adhesion molecules as a means of exploiting the underlying signaling pathways, entering into host cells or establishing extracellular persistence. Often, bacteria are able to bind to cell adhesion molecules by mimicking or acting in place of host cell receptors or their ligands. Recent studies have contributed to our understanding of bacterial adherence mechanisms and the consequences of receptor engagement; they have also highlighted alternative functions of cell adhesion molecules. [Copyright &y& Elsevier]

Adhesion molecules, although catalytically inactive, are able to translate environmental cues into complex intracellular signals. They can do this by associating with tyrosine kinase receptors for growth factors, which can prime, integrate or feedback adhesion-based signals. Recent results show that reciprocal crosstalk between the two systems is only one facet of such a collaboration, and that unconventional and alternative hierarchies can be established in which, on the one hand, cell adhesion can trigger ligand-independent activation of growth factor receptors, and, on the other, growth factors can induce adhesion molecules to propagate adhesion-independent signals. [Copyright &y& Elsevier]

Mental actions are based on the dynamic organization of neuronal networks. In particular, phylogenetically young brain areas (e.g., cortical associative circuits) involved in the realization of higher brain functions are continuously re-adjusted to meet environmental demands. The mechanisms of synaptic plasticity, i.e., of structural stabilization and labilization underlying a life-long synaptic remodelling, are largely based on external morphoregulatory cues and internal signalling pathways that non-neuronal cells have phylogenetically acquired to sense their relationship to the local neighbourhood and to control after development is completed proliferation and differentiation in the process of tissue repair and regeneration. After having withdrawn from the cell cycle, differentiated neurons are, thus, able to use molecular mechanisms primarily developed to control proliferation alternatively to control synaptic plasticity. The existence of these alternative effector pathways within a neuron puts it at risk to erroneously convert signals derived from plastic synaptic changes into positional cues that will activate the cell cycle. This cell cycle activation potentially links synaptic plasticity to cell death. Preventing cell cycle activation by locking neurons in a differentiated but still highly plastic phenotype will, thus, be crucial to prevent neurodegeneration. [Copyright &y& Elsevier]

It is increasingly apparent that oxidants can play an important role in mediating specific cell responses and expression of genes involved in degenerative pathophysiologic states, such as inflammation. In particular, oxidant-induced activation of the multisubunit nuclear transcription factor, NFκB, has been implicated in the transcriptional upregulation of inflammatory genes like endothelial cell adhesion glycoproteins. A second emerging concept is the recognition that the oxidant effects in cellular and molecular regulation may be mediated by oxidant-induced loss of cellular oxidation-reduction (redox) balance. This review will provide an overview of our current understanding of leukocyte-endothelial cell interactions derived from in vitro studies of endothelial cell monolayers exposed to anoxia/reoxygenation, with specific emphasis on the molecular determinants mediating this inflammatory process and the contribution of reoxygenation-induced cellular redox imbalance to the activation of NFκB and the expression of endothelial surface adhesion molecules. [Copyright &y& Elsevier]