The hypocretins/orexins: novel hypothalamic neuropeptides involved in different physiological systems

The hypothalamus regulates diverse physiological functions, including the control of energy metabolism, circadian rhythms, stress and anxiety, sexual and reproductive behaviors. An overview of the most prevalent hypothalamus-enriched mRNAs revealed that this area of the brain specializes in producing intercellular signaling molecules. Two new secreted peptides derived from a single neuropeptide precursor, named hypocretins and orexins by two different groups, are synthesized in a small set of neurons in the perifornical area of the hypothalamus. Intracerebroventricular injection of the hypocretins/orexins increases food consumption in rats. Here we review recent progress in identifying the role of the hypocretins/orexins in the control of energy balance and in other physiological systems.     

Integrin antagonists

Integrins are a family of cell surface glycoproteins that mediate numerous cell-cell and cell-matrix interactions and are involved in biological processes such as tissue morphogenesis, leukocyte recirculation and migration, wound healing, blood clotting and immune response. Aberrant cell adhesion has been implicated in the pathogenesis of several diseases, including a number of inflammatory disorders such as rheumatoid arthritis, inflammatory bowel disease and asthma, as well as cancer and coronary heart disease. As such integrins are seen as excellent targets for the development of therapeutic agents. This report begins with an examination of the structure of integrin molecules and their ligands and then goes on to review the current state of development of antiintegrin antagonists. Received 13 April 1999; received after revision 28 May 1999; accepted 28 May 1999     

Kinesin-II, the heteromeric kinesin

The kinesins constitute a large family of motor proteins which are responsible for the distribution of numerous organelles, vesicles and macromolecular complexes throughout the cell. One class of these molecular motors, kinesin-II, is unique in that these proteins are typically found as heterotrimeric complexes containing two different, though related, kinesin-like motor subunits, and a single nonmotor subunit. The heteromeric nature of these kinesins appears to have resulted in a class of combinatorial kinesins which can 'mix and match' different motor subunits. Another novel feature of these motors is that the activities of several kinesin-II representatives are essential in the assembly of motile and nonmotile cilia, a role not attributed to any other kinesin. This review presents a brief overview of the structure and biological functions of kinesin-II, the heteromeric kinesin.     

The pleiotropic functions of aspirin: mechanisms of action

Recent studies have suggested that aspirin and aspirin-like compounds have a variety of actions in addition to their well-studied ability to inhibit cyclooxygenases. These actions include inhibition of the uncoupling of oxidative phosphorylation, decreases in adenosine triphosphate stores, increases in extracellular adenosine, downregulation of the expression and activity of inducible nitric oxide synthetase, inhibition and/or stimulation of various mitogen-activated protein kinase activities and inhibition of nuclear factor binding κB site (NF-κB) activation. Moreover, aspirin-like compounds have recently been shown to have previously unappreciated clinical and biological effects, some apparently independent of cyclooxygenase. In this review we discuss the various mechanisms of action of aspirin-like compounds and their relevance to clinical disease and therapy. Received 1 February 1999; received after revision 1 April 1999; accepted 7 May 1999     

Ventral neural tube cells differentiate into hepatocytes in the chick embryo

A population of ventral neural tube cells has recently been shown to migrate out of the hind brain neural tube via the vagus nerve and contribute to the developing gastrointestinal tract. Since liver is also innervated by the vagus nerve, we sought to determine if these cells also migrate into the liver. Ventral neural tube cells in the caudal hindbrain of chick embryos were tagged with a replication-deficient retroviral vector containing the LacZ gene on embryonic day 2. Embryos were processed for detection of labeled cells on embryonic day 5 and 11. Labeled cells were seen in the liver on both days and identified as hepatocytes. Previously, it was believed that all hepatocytes develop from the gut endoderm. Results of the present study show an additional source for the formation of liver cells. Received 25 August 1998; received after revision 5 November 1998; accepted 5 November 1998     

Eukaryotic glycosylation: whim of nature or multipurpose tool?

Protein and lipid glycosylation is a ubiquitous phenomenon. The task of cataloguing the great structural variety of the glycan part has demanded considerable efforts over decades. This patient endeavor was imperative to discern the inherent rules of glycosylation which cannot affirm assumptions on a purely coincidental nature of this type of protein and lipid modification. These results together with theoretical considerations uncover a salient property of oligosaccharides. In comparison with amino acids and nucleotides, monosaccharides excel in their potential to serve as units of hardware for storing biological information. Thus, the view that glycan chains exclusively affect physiochemical properties of the conjugates is indubitably flawed. This original concept has been decisively jolted by the discovery of endogenous receptors (lectins) for distinct glycan epitopes which are as characteristic as a fingerprint or a signature for a certain protein (class) or cell type. Recent evidence documents that these binding proteins are even endowed with the capacity to select distinct low-energy conformers of the often rather flexible oligosaccharides, granting entry to a new level of regulation of ligand affinity by shifting conformer equilibria. The assessment of the details of this recognition by X-ray crystallography, nuclear magnetic resonance spectroscopy, microcalorimetry and custom-made derivatives is supposed to justify a guarded optimism in satisfying the need for innovative drug design in antiadhesion therapy, for example against viral or bacterial infections and unwanted inflammation. This review presents a survey of the structural aspects of glycosylation and of evidence to poignantly endorse the notion that carrier-attached glycan chains can partake in biological information transfer at the level of cell compartments, cells and organs.     

Signalling via caveolin: involvement in the cross-talk between phosphoinositolglycans and insulin

In recent years, a number of cross-talk systems have been identified which feed into the insulin signalling cascade at the level of insulin receptor substrate (IRS) tyrosine phosphorylation, e.g., receptor and non-receptor tyrosine kinases and G-protein-coupled receptors. At the molecular level, a number of negative modulator and feedback systems somehow interacting with the beta-subunit (catecholamine-, phorbolester-, or tumor necrosis factor-alpha-induced serine/threonine phosphorylation, carboxy-terminal trimming by a thiol-dependent protease, association of inhibitory/regulatory proteins such as RAD, PC1, PED, alpha2-HS-glycoprotein) have been identified as candidate mechanisms for the impairment of insulin receptor function by elevations in the activity and/or amount of the corresponding modification enzymes/inhibitors. Both decreased responsiveness and sensitivity of the insulin receptor beta-subunit for insulin-induced tyrosine autophosphorylation have been demonstrated in several cellular and animal models of metabolic insulin resistance as well as in the adipose tissue and skeletal muscle of diabetic patients and obese Pima Indians compared to non-obese subjects. Therefore, induction of the insulin signalling cascade by bypassing the defective insulin receptor kinase may be useful for the therapy of non-insulin dependent diabetes mellitus. During the past two decades, phosphoinositolglycans (PIGs) of various origin have been demonstrated to exert potent insulin-mimetic metabolic effects upon incubation with cultured or isolated muscle and adipose cells. However, it remained to be elucidated whether these compounds actually manage to trigger insulin signalling and if so at which level of hierarchy within the signalling cascade the site of interference is located. Recent studies using isolated rat adipocytes and chemically synthesized PIG compounds point to IRS1/3 tyrosine phosphorylation by p59Lyn kinase as the site of cross-talk, the negative regulation of which by interaction with caveolin is apparently abrogated by PIG. This putative mechanism is thus compatible with the recently formulated caveolin signalling hypothesis, the supporting data for which are reviewed here. Though we have not obtained experimental evidence for the involvement of PIG in physiological insulin action, the potential cross-talk between insulin and PIG signalling, including the caveolae/detergent-insoluble glycolipid-enriched rafts as the compartments where the corresponding signalling components are concentrated, thus represent novel targets for signal transduction therapy.     

Notch signalling pathway mediates hair cell development in mammalian cochlea

The mammalian cochlea contains an invariant mosaic of sensory hair cells and non-sensory supporting cells reminiscent of invertebrate structures such as the compound eye in Drosophila melanogaster. The sensory epithelium in the mammalian cochlea (the organ of Corti) contains four rows of mechanosensory hair cells: a single row of inner hair cells and three rows of outer hair cells. Each hair cell is separated from the next by an interceding supporting cell, forming an invariant and alternating mosaic that extends the length of the cochlear duct. Previous results suggest that determination of cell fates in the cochlear mosaic occurs via inhibitory interactions between adjacent progenitor cells (lateral inhibition). Cells populating the cochlear epithelium appear to constitute a developmental equivalence group in which developing hair cells suppress differentiation in their immediate neighbours through lateral inhibition. These interactions may be mediated through the Notch signalling pathway, a molecular mechanism that is involved in the determination of a variety of cell fates. Here we show that genes encoding the receptor protein Notch1 and its ligand, Jagged 2, are expressed in alternating cell types in the developing sensory epithelium. In addition, genetic deletion of Jag2 results in a significant increase in sensory hair cells, presumably as a result of a decrease in Notch activation. These results provide direct evidence for Notch-mediated lateral inhibition in a mammalian system and support a role for Notch in the development of the cochlear mosaic.     

Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease

Darier disease (DD) is an autosomal-dominant skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. Recently we constructed a 2.4-Mb, P1-derived artificial chromosome contig spanning the DD candidate region on chromosome 12q23-24.1. After screening several genes that mapped to this region, we identified mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca2(+)-ATPase type 2 isoform (SERCA2) and is highly expressed in keratinocytes. Thirteen mutations were identified, including frameshift deletions, in-frame deletions or insertions, splice-site mutations and non-conservative missense mutations in functional domains. Our results demonstrate that mutations in ATP2A2 cause DD and disclose a role for this pump in a Ca(2+)-signalling pathway regulating cell-to-cell adhesion and differentiation of the epidermis.