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.     

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.     

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.     

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.     

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.     

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.     

IGF2: epigenetic regulation and role in development and disease

Insulin-like growth factor II (IGF2) is perhaps the most intricately regulated of all growth factors characterized to date. Its gene is imprinted – only one allele is active, depending on parental origin – and this pattern of expression is maintained epigenetically in almost all tissues. IGF2 activity is further controlled through differential expression of receptors and IGF-binding proteins (IGFBPs) that determine protein availability. This complex and multifaceted regulation emphasizes the importance of accurate IGF2 expression and activity. This review will examine the regulation of the IGF2 gene and what it has revealed about the phenomenon of imprinting, which is frequently disrupted in cancer. IGF2 protein function will be discussed, along with diseases that involve IGF2 overexpression. Roles for IGF2 in sonic hedgehog (Shh) signaling and angiogenesis will also be explored.     

The function of GPI-anchored proteins in T cell development, activation and regulation of homeostasis

Many glycosylphosphatidyl-inositol-anchored proteins (GPI-AP) are expressed on T lymphocytes. Ligand or mAb-mediated aggregation of all GPI-AP tested to date results in the initiation of signal transduction pathways via the activation of src family protein tyrosine kinases. Src family kinases co-localise with GPI-AP in specialised sub-domains of the plasma membrane, referred to as detergent insoluble membrane microdomains (DIGS), which are thought to function as signalling platforms. GPI-AP may play a role in the regulation of T cell clonal expansion and effector functions at multiple levels, including the initiation of T cell activation through the antigen receptor complex, the regulation of ongoing responses supported by persisting antigen, as well as proliferative responses to the major T cell growth factor, IL-2. Evidence supporting the role of GPI-AP in the regulation of T cell development, activation and homeostasis is discussed, as well as insights provided by studies in humans and mice lacking GPI-AP.     

Genetic regulation of osteoclast development and function

Osteoclasts are the principal, if not exclusive, bone-resorbing cells, and their activity has a profound impact on skeletal health. So, disorders of skeletal insufficiency, such as osteoporosis, typically represent enhanced osteoclastic bone resorption relative to bone formation. Prevention of pathological bone loss therefore depends on an appreciation of the mechanisms by which osteoclasts differentiate from their precursors and degrade the skeleton. The past five years have witnessed important insights into osteoclast formation and function. Many of these discoveries have been made through genetic experiments that involved the rare hereditary disorder osteopetrosis.