Oligodendrocyte progenitor cell fate and function in development and disease

Differentiation of oligodendrocyte progenitor cells (OPCs) into myelination-capable mature oligodendrocytes is essential for proper function of the central nervous system. OPCs are tissue-resident stem cells that populate all regions of the central nervous system and exist beyond development into adulthood. Disorders that lead to disruption of this critical cell state change cause devastating myelin diseases that are often associated with shortened life span. Recent findings have also provided support for a newly appreciated contribution of perturbed OPC differentiation to neurodegenerative and psychiatric diseases. These findings emphasize the need for a more complete understanding of OPC differentiation in health and disease. Here, we review recent molecular and functional findings revealing new roles of OPCs. It is our hope that this review provides readers with an enticing snapshot of current OPC research and highlights the potential of controlling OPC fate and function to treat diseases of the brain.     

Integrin function and regulation in development

Integrins are a large family of membrane receptors, consisting of alpha and beta subunits, that play a pivotal role in the interaction of cells with the extracellular matrix. Such interaction regulates the organization of cells in organs and tissues during development as well as cell differentiation and proliferation. We have shown that unfertilized oocytes express integrins that might be important during fertilization. We also analyzed nervous system and muscle tissue development showing that integrin expression is precisely regulated during organization of these tissues. The results indicate that two distinct integrin alpha subunits mediate the outgrowth of processes in nerve and glial cells. Alpha1 integrin, a laminin receptor, is up-regulated by nerve growth factor and other differentiation stimuli and is involved in neurite extension by nerve cells. In contrast, process extension by glial cells is likely to involve the alphaV integrin. Moreover, the latter integrin subunit is also transiently expressed in muscle of the embryo body where it localizes predominantly at developing myotendinous junctions. After birth this integrin disappears and is substituted by the alpha7 subunit. At the same time, important changes also occur in the expression of the associated beta subunit. In fact, the beta1A isoform which is expressed in fetal muscles, is substituted by beta1D. These isoforms are generated by alternative splicing and differ in only a few amino acid residues at the COOH terminus of the protein. This region of the molecule is exposed at the cytoplasmic face of the plasma membrane and is connected to the actin filaments. Our results show that beta1D, which is expressed only in striated muscle tissues, binds to both cytoskeletal and extracellular matrix proteins with an affinity higher than beta1A. Thus, beta1D provides a stronger link between the cytoskeleton and extracellular matrix necessary to support mechanical tension during muscle contraction. These results indicate that cells can regulate their interactions with the extracellular matrix by changing their expression of alpha integrin subunits and thus ligand specificity, or by more subtle changes involving alternative usage of different cytoplasmic domains. The important role of both alpha and beta integrin subunit cytoplasmic domains during development is further illustrated by the analysis of targeted mutations which we have generated by homologous recombination in mice.     

The role of nuclear pores in gene regulation,development and disease

Nuclear‐pore complexes (NPCs) are large protein channels that span the nuclear envelope (NE), which is a double membrane that encloses the nuclear genome of eukaryotes. Each of the typically 2,000–4,000 pores in the NE of vertebrate cells is composed of multiple copies of 30 different proteins known as nucleoporins. The evolutionarily conserved NPC proteins have the well‐characterized function of mediating the transport of molecules between the nucleoplasm and the cytoplasm. Mutations in nucleoporins are often linked to specific developmental defects and disease, and the resulting phenotypes are usually interpreted as the consequences of perturbed nuclear transport activity. However, recent evidence suggests that NPCs have additional functions in chromatin organization and gene regulation, some of which might be independent of nuclear transport. Here, we review the transport‐dependent and transport‐independent roles of NPCs in the regulation of nuclear function and gene expression.     

Adjuvant regulation of T cell function.

The effect of complete Freund's adjuvant (CFA) on distinct T cell functions was investigated. Adjuvant was found to suppress the generation of cytolytic T cells in vivo when mixed with allogeneic P815 cells before immunization of C57BL/6 mice. Inoculation of the mice with either adjuvant or adjuvant emulsified with allogeneic cells resulted in whole splenic populations or immunoabsorbent-purified T cells that did not generate cytolytic activity in vitro against allogeneic cells. Mixing T cells from normal and adjuvant-treated mice before in vitro sensitization resulted in suppression of lytic activity. However, memory T cells were not subject to the same suppressive regulation as were precytotoxic T cells since adjuvant had no effect on subsequent boosting of memory.     

Cytokine regulation of endothelial cell function.

Endothelial cells have long been viewed as a passive lining of blood vessels endowed essentially with negative properties such as that of being nonreactive to blood components. It is now evident that upon exposure to environmental signals, cytokines in particular, vascular cells undergo profound changes in gene expression and function that allow these cells to participate actively in inflammatory reactions, immunity, and thrombosis. Different mediators (e.g., interleukin-1 [IL-1] and interferon-gamma) activate relatively distinct sets of functions. These functional programs expressed in activated endothelial cells include the production by the same cells of cytokines (e.g., IL-1, IL-6, chemotactic cytokines, and colony-stimulating factors), which regulate hematopoiesis, the differentiation and proliferation of T and B lymphocytes, and the extravasation of leukocytes. The identification of cytokine circuits through which vascular cells participate to thrombotic, inflammatory, and immune reactions provides novel targets for therapeutic intervention.     

Tenascin-C and the development of articular cartilage

In comparison to the vast literature on articular cartilage structure and function, relatively little is known about how articular cartilage forms during embryo-genesis and is endowed with unique phenotypic properties, most notably the ability to persist and function throughout postnatal life. In this minireview, we summarize recent studies from our laboratory suggesting that the extracellular matrix protein tenascin-C is involved in the genesis and function of articular chondrocytes. These and other data have led us to propose that tenascin-C may be part of in vivo mechanisms whereby articular chondrocytes develop at the epiphysis of long bone models, remain functional throughout postnatal life, and avoid the endochondral ossification process undertaken by the bulk of chondrocytes located in the metaphysis and diaphysis of skeletal models.     

Bone cell biology: the regulation of development, structure, and function in the skeleton

Bone cells compose a population of cells of heterogeneous origin but restricted function with respect to matrix formation, mineralization, and resorption. The local, mesenchymal origin of the cells which form the skeleton contrasts with their extraskeletal, hemopoietic relatives under which bone resorption takes place. However, the functions of these two diverse populations are remarkably related and interdependent. Bone cell regulation, presently in its infancy, is a complicated cascade involving a plethora of local and systemic factors, including some components of the skeletal matrices and other organ systems. Thus, any understanding of bone cell regulation is a key ingredient in understanding not only the development, maintenance, and repair of the skeleton but also the prevention and treatment of skeletal disorders.     

Neuroendocrine function in Huntington's disease: dopaminergic regulation of prolactin release.

Plasma prolactin levels were measured in 7 patients with Huntington's disease (HD) and 8 age matched controls after the random, oral administration of 1) placebo, 2) chlorpromazine 100 mg, 3) carbidopa 50 mg followed by levodopa 200 mg, and 4) bromocriptine 1 mg. After placebo, HD patients had significantly higher prolactin levels than controls at all times except 180, 240, and 360 minutes. Controls showed a significant suppression of prolactin release at 180 and 240 minutes after levodopa/carbidopa and at 180, 240, and 360 minutes after bromocriptine. In contrast, HD patients demonstrated no change after both levodopa/carbidopa and bromocriptine. Both groups showed a sustained elevation after CPZ, but despite having an initially higher baseline and an earlier response, the maximum prolactin levels of HD patients were significantly less than those of controls.This data suggest that HD patients may have a diminished number of hypothalamic-pituitary dopamine receptors for the regulation PRL secretion.     

From gene regulation to gene function: regulatory networks in bacillus subtilis

Bacillus subtilis is a sporulating Gram-positive bacterium that lives primarily in the soil and associated water sources. The publication of the B. subtilis genome sequence and subsequent systematic functional analysis and gene regulation programmes, together with an extensive understanding of its biochemistry and physiology, makes this micro-organism a prime candidate in which to model regulatory networks in silico. In this paper we discuss combined molecular biological and bioinformatical approaches that are being developed to model this organism's responses to changes in its environment.     

Conservation and diversification of gene function in plant development.

The Arabidopsis genome sequence has given us an inventory of the genes needed to specify a flowering plant. Plants are highly diverse in appearance and the mechanisms whereby this diversity has arisen need explanation. A fundamental question is to what extent diversity arises from remodelling of gene function or relocation of gene pathways, rather than from the gain or loss of genes. Similar types of genetic rewiring may be responsible for both intra- and inter-specific differences in developmental processes. Recent advances in the understanding of shoot, flower and leaf development provide insights to this question.