Differential roles of multiple adhesion molecules in cell migration: granule cell migration in cerebellum

The migration of cerebellar granule cells from the external granular layer to the internal granular layer is mediated by the radical Bergmann glial fiber. Recent works have shown that cell adhesion molecules, extra-cellular matrix proteins and proteolytic enzymes or their activators are involved in this process. Immuno-localization studies showed differential temporal and spatial expression patterns of different adhesion molecules, their isoforms, and post-translational modification during different stages of granule cell migration. Functional perturbation experiments using cerebellar explant cultures demonstrated that several adhesion molecules as well as plasminogen activator are involved in granule cell migration and are required in different stages. Other systems used to study granule cell migration including dissociated microwell cultures and granule cell deficient mouse mutants are discussed in the context of adhesion molecules. The results accumulated so far suggest that the migration of granule cells is a complex process in which the cooperation of a group of molecules with different functions, some for adhesion some for de-adhesion, are required to fulfill the different needs during the migratory course.     

Ethanol impairs insulin-stimulated mitochondrial function in cerebellar granule neurons

Ethanol impairs insulin-stimulated survival and mitochondrial function in immature proliferating neuronal cells due to marked inhibition of downstream signaling through P13 kinase. The present study demonstrates that, in contrast to immature neuronal cells, the major adverse effect of chronic ethanol exposure (50 mM) in post-mitotic rat cerebellar granule neurons is to inhibit insulin-stimulated mitochondrial function (MTT activity, MitoTracker Red fluorescence, and cytochrome oxidase immunoreactivity). Ethanol-impaired mitochondrial function was associated with increased expression of the p53 and CD95 pro-apoptosis genes, reduced Calcein AM retention (a measure of membrane integrity), increased SYTOX Green and propidium iodide uptake (indices of membrane permeability), and increased oxidant production (dihydrorosamine fluorescence and H2O2 generation). The findings of reduced membrane integrity and mitochondrial function in short-term (24 h) ethanol-exposed neurons indicate that these adverse effects of ethanol can develop rapidly and do not require chronic neurotoxic injury. A role for caspase activation as a mediator of impaired mitochondrial function was demonstrated by the partial rescue observed in cells that were pre-treated with broad-spectrum caspase inhibitors. Finally, we obtained evidence that the inhibitory effects of ethanol on mitochondrial function and membrane integrity were greater in insulin-stimulated compared with nerve growth factor-stimulated cultures. These observations suggest that activation of insulin-independent signaling pathways, or the use of insulin sensitizer agents that enhance insulin signaling may help preserve viability and function in neurons injured by gestational exposure to ethanol.     

Recent advances in the genetics of schizophrenia

The genetic etiology of schizophrenia, a common and debilitating psychiatric disorder, is supported by a wealth of data. Review of the current findings suggests that considerable progress has been made in recent years, with a number of chromosomal regions consistently implicated by linkage analysis. Three groups have shown linkage to 1q21-22 using similar models, with HLOD scores of 6.5, 3.2, and 2.4. Other replicated loci include 13q32 that has been implicated by two independent groups with significant HLOD scores (4.42) or NPL values (4.18), and 5p14.1-13.1, 5q21-33, 8p21-22, and 10p11-15, each of which have been reported as suggestive by at least three separate groups. Different studies have also replicated evidence for a modest number of candidate genes that were not ascertained through linkage. Of these, the greatest support exists for the DRD3 (3q13.3), HTR2A (13q14.2), and CHRNA7 (15q13-q14) genes. The refinement of phenotypes, the use of endophenotypes, reduction of heterogeneity, and extensive genetic mapping have all contributed to this progress. The rapid expansion of information from the human genome project will likely further accelerate this progress and assist in the discovery of susceptibility genes for schizophrenia. A greater understanding of disease mechanisms and the application of pharmacogenetics should also lead to improvements in therapeutic interventions. Received 11 May 2001; received after revision: 20 July 2001; accepted 18 September 2001     

The ubiquitin-proteasome system and chromosome 17 in cerebellar granule cells and medulloblastoma subgroups

Chromosome 17 abnormalities are often observed in medulloblastomas (MBs), particularly those classified in the consensus Groups 3 and 4. Herein we review MB signature genes associated with chromosome 17 and the relationship of these signature genes to the ubiquitin-proteasome system. While clinical investigators have not focused on the ubiquitin-proteasome system in relation to MB, a substantial amount of data on the topic has been hidden in the form of supplemental datasets of gene expression. A supplemental dataset associated with the Thompson classification of MBs shows that a subgroup of MB with 17p deletions is characterized by reduced expression of genes for several core particle subunits of the beta ring of the proteasome (β1, β4, β5, β7). One of these genes (PSMB6, the gene for the β1 subunit) is located on chromosome 17, near the telomeric end of 17p. By comparison, in the WNT group of MBs only one core proteasome subunit, β6, associated with loss of a gene (PSMB1) on chromosome 6, was down-regulated in this dataset. The MB subgroups with the worst prognosis have a significant association with chromosome 17 abnormalities and irregularities of APC/C cyclosome genes. We conclude that the expression of proteasome subunit genes and genes for ubiquitin ligases can contribute to prognostic classification of MBs. The therapeutic value of targeting proteasome subunits and ubiquitin ligases in the various subgroups of MB remains to be determined separately for each classification of MB.     

Recent advances of tissue culture in cancer research

Résumé On donne ici un bref exposé des principaux courants d'idée qui se rattachent surtout à la recherche anticancereuse telle qu'elle a été abordée depuis la seconde guerre modiale par la méthode des cultures de tissus. De grands progrès techniques ont aujourd'hui rendu possible la manipulation en masse de la cellule de mammifères en cultures continues, cellule traitée essentiellement comme microorganisme. Toutefois, comme les cellules à croissance rapide autant d'origine normale que maligne perdent leurs caractères individuels et finissent par se ressembler, l'intérêt se reporte actuellement sur les cultures de tissus organisés, où les facteurs favorables à la différenciation et au contrôle de la croissance peuvent être examinés.     

Recent advances in the development of new transgenic animal technology

Transgenic animal technology is one of the fastest growing biotechnology areas. It is used to integrate exogenous genes into the animal genome by genetic engineering technology so that these genes can be inherited and expressed by offspring. The transgenic efficiency and precise control of gene expression are the key limiting factors in the production of transgenic animals. A variety of transgenic technologies are available. Each has its own advantages and disadvantages and needs further study because of unresolved technical and safety issues. Further studies will allow transgenic technology to explore gene function, animal genetic improvement, bioreactors, animal disease models, and organ transplantation. This article reviews the recently developed animal transgenic technologies, including the germ line stem cell-mediated method to improve efficiency, gene targeting to improve accuracy, RNA interference-mediated gene silencing technology, zinc-finger nuclease gene targeting technology and induced pluripotent stem cell technology. These new transgenic techniques can provide a better platform to develop transgenic animals for breeding new animal varieties and promote the development of medical sciences, livestock production, and other fields.     

Introduction: Recent advances in comparative physiology of cardiovascular control

The Editors wish to thank Prof. R. B. Hill for having coordinated this Multi-author Review.     

Differential roles of multiple adhesion molecules in cell migration: Granule cell migration in cerebellum

Summary The migration of cerebellar granule cells from the external granular layer to the internal granular layer is mediated by the radial Bergmann glial fiber. Recent works have shown that cell adhesion molecules, extra-cellular matrix proteins and proteolytic enzymes or their activators are involved in this process. Immuno-localization studies showed differential temporal and spatial expression patterns of different adhesion molecules, their isoforms, and post-translational modification during different stages of granule cell migration. Functional perturbation experiments using cerebellar explant cultures demonstrated that several adhesion molecules as well as plasminogen activator are involved in granule cell migration and are required in different stages. Other systems used to study granule cell migration including dissociated microwell cultures and granule cell deficient mouse mutants are discussed in the context of adhesion molecules. The results accumulated so far suggest that the migration of granule cells is a complex process in which the cooperation of a group of molecules with different functions, some for adhesion some for de-adhesion, are required to fulfill the different needs during the migratory course.     

Tumor cell migration in complex microenvironments

Tumor cell migration is essential for invasion and dissemination from primary solid tumors and for the establishment of lethal secondary metastases at distant organs. In vivo and in vitro models enabled identification of different factors in the tumor microenvironment that regulate tumor progression and metastasis. However, the mechanisms by which tumor cells integrate these chemical and mechanical signals from multiple sources to navigate the complex microenvironment remain poorly understood. In this review, we discuss the factors that influence tumor cell migration with a focus on the migration of transformed carcinoma cells. We provide an overview of the experimental and computational methods that allow the investigation of tumor cell migration, and we highlight the benefits and shortcomings of the various assays. We emphasize that the chemical and mechanical stimulus paradigms are not independent and that crosstalk between them motivates the development of new assays capable of applying multiple, simultaneous stimuli and imaging the cellular migratory response in real-time. These next-generation assays will more closely mimic the in vivo microenvironment to provide new insights into tumor progression, inform techniques to control tumor cell migration, and render cancer more treatable.     

Mechanisms of endothelial cell migration

Cell migration plays a central role in a variety of physiological and pathological processes during our whole life. Cellular movement is a complex, tightly regulated multistep process. Although the principle mechanisms of migration follow a defined general motility cycle, the cell type and the context of moving influences the detailed mode of migration. Endothelial cells migrate during vasculogenesis and angiogenesis but also in a damaged vessel to restore vessel integrity. Depending on the situation they migrate individually, in chains or sheets and complex signaling, intercellular signals as well as environmental cues modulate the process. Here, the different modes of cell migration, the peculiarities of endothelial cell migration and specific guidance molecules controlling this process will be reviewed.     

Principles of neural cell migration

Summary A basic property of immature neurons is their ability to change position from the place of their final mitotic division in proliferative centers of the developing brain to the specific positions they will occupy in a given structure of the adult nervous system. Proper acquisition of neuron position, attained through the process of active migration, ultimately affects a cell's morphology, synaptic connectivity and function. Although various classes of neurons may use different molecular cues to guide their migration to distant structures, a surface-mediated interaction between neighboring cells is considered essential for all types of migration. Disturbance of this cell-cell interaction may be important in several congenital and/or acquired brain abnormalities. The present article considers the basic mechanisms and principles of neuronal cell migration in the mammalian central nervous system.     

Numerical capacities of cerebellar cell and fiber systems

Zusammenfassung Mit Bezug auf Probleme der Kybernetik wurde die Informationsübertragungskapazität der afferenten und efferenten Zell- und Fasersysteme des menschlichen Kleinhirns numerisch definiert.