Recent advances in cerebellar granule cell migration

In the developing brain, postmitotic neurons exhibit dynamic changes in mode, direction, tempo and rate of migration as they traverse different cortical layers. Such changes in cell migration require orchestrated activities of multiple guidance cues and transmembrane signals. In this article, we first describe when, where and how cerebellar granule cells alter their migratory behavior during the entire course of their migration. We then present how internal (inherent) programs regulate the sequential changes in the migratory behavior of granule cells in vitro. Finally, we discuss the roles of external guidance cues and transmembrane signals in controlling granule cell migration.     

Dual effect of cannabinoid CB<Subscript>1</Subscript> receptor stimulation on a vanilloid VR1 receptor-mediated response

Cannabinoid CB1 receptors and vanilloid VR1 receptors are co-localized to some extent in sensory neurons of the spinal cord and dorsal root ganglia. In this study, we over-expressed both receptor types in human embryonic kidney (HEK)-293 cells and investigated the effect of the CB1 agonist HU-210 on the VR1-mediated increase in intracellular Ca2+ ([Ca2+]i), a well-known response of the prototypical VR1 agonist capsaicin. After a 5-min pre-treatment, HU-210 (0.1 microM) significantly enhanced the effect of several concentrations of capsaicin on [Ca2+]i in HEK-293 cells over-expressing both rat CB1 and human VR1 (CB1-VR1-HEK cells), but not in cells over-expressing only human VR1 (VR1-HEK cells). This effect was blocked by the CB1 receptor antagonist SR141716A (0.5 microM), and by phosphoinositide-3-kinase and phospholipase C inhibitors. The endogenous agonist of CB1 and VR1 receptors, anandamide, was more efficacious in inducing a VR1-mediated stimulation of [Ca2+]i in CB1-VR1-HEK cells than in VR1-HEK cells, and part of its effect on the former cells was blocked by SR141716A (0.5 microM). Pre-treatment of CB1-VR1-HEK cells with forskolin, an adenylate cyclase activator, enhanced the capsaicin effect on [Ca2+]i. HU-210, which in the same cells inhibits forskolin-induced enhancement of cAMP levels, blocked the stimulatory effect of forskolin on capsaicin. Our data suggest that in cells co-expressing both CB1 and VR1 receptors, pre-treatment with CB1 agonists inhibits or stimulates VR1 gating by capsaicin depending on whether or not cAMP-mediated signalling has been concomitantly activated.     

Isoprenoid biosynthesis in hereditary periodic fever syndromes and inflammation

Mevalonate kinase (MK) is an essential enzyme in the isoprenoid biosynthesis pathway which produces numerous biomolecules (isoprenoids) involved in a variety of cellular processes. The indispensability of MK and isoprenoid biosynthesis for human health is demonstrated by the identification of its deficiency as the biochemical and molecular cause of the inherited autoinflammatory disorders mevalonic aciduria and hyperimmunoglobulinemia D and periodic fever syndrome. Since the discovery of the genetic defect, considerable progress has been made in understanding the molecular, biochemical and immunological basis of MK deficiency. Important questions such as which specific protein(s) and/or signaling pathway(s) are affected, however, remain unanswered. Resolving the complete pathophysiology of this disorder is a major challenge, but eventually will give insight into the in vivo role of MK and isoprenoid biosynthesis in inflammation and fever. This may open novel options for antiinflammatory therapies in general. Here, we give a general introduction on isoprenoid biosynthesis, the regulation thereof and deficiencies therein. We review the molecular, biochemical and immunological aspects of MK deficiency and discuss the relations between isoprenoid biosynthesis and inflammation. Finally, we compare MK deficiency with other autoinflammatory syndromes.     

The microRNA-producing enzyme Dicer1 is essential for zebrafish development

MicroRNAs (miRNAs) are produced by the Dicer1 enzyme; the role of Dicer1 in vertebrate development is unknown. Here we report target-selected inactivation of the dicer1 gene in zebrafish. We observed an initial build-up of miRNA levels, produced by maternal Dicer1, in homozygous dicer1 mutants, but miRNA accumulation stopped after a few days. This resulted in developmental arrest around day 10. These results indicate that miRNA-producing Dicer1 is essential for vertebrate development.     

Interaction of reelin signaling and Lis1 in brain development

Loss-of-function mutations in RELN (encoding reelin) or PAFAH1B1 (encoding LIS1) cause lissencephaly, a human neuronal migration disorder. In the mouse, homozygous mutations in Reln result in the reeler phenotype, characterized by ataxia and disrupted cortical layers. Pafah1b1(+/-) mice have hippocampal layering defects, whereas homozygous mutants are embryonic lethal. Reln encodes an extracellular protein that regulates layer formation by interacting with VLDLR and ApoER2 (Lrp8) receptors, thereby phosphorylating the Dab1 signaling molecule. Lis1 associates with microtubules and modulates neuronal migration. We investigated interactions between the reelin signaling pathway and Lis1 in brain development. Compound mutant mice with disruptions in the Reln pathway and heterozygous Pafah1b1 mutations had a higher incidence of hydrocephalus and enhanced cortical and hippocampal layering defects. Dab1 and Lis1 bound in a reelin-induced phosphorylation-dependent manner. These data indicate genetic and biochemical interaction between the reelin signaling pathway and Lis1.     

Fingerprints of global warming on wild animals and plants

Over the past 100 years, the global average temperature has increased by approximately 0.6 degrees C and is projected to continue to rise at a rapid rate. Although species have responded to climatic changes throughout their evolutionary history, a primary concern for wild species and their ecosystems is this rapid rate of change. We gathered information on species and global warming from 143 studies for our meta-analyses. These analyses reveal a consistent temperature-related shift, or 'fingerprint', in species ranging from molluscs to mammals and from grasses to trees. Indeed, more than 80% of the species that show changes are shifting in the direction expected on the basis of known physiological constraints of species. Consequently, the balance of evidence from these studies strongly suggests that a significant impact of global warming is already discernible in animal and plant populations. The synergism of rapid temperature rise and other stresses, in particular habitat destruction, could easily disrupt the connectedness among species and lead to a reformulation of species communities, reflecting differential changes in species, and to numerous extirpations and possibly extinctions.     

Quasi-phase-matched generation of coherent extreme-ultraviolet light

High-harmonic generation is a well-known method of producing coherent extreme-ultraviolet (EUV) light, with photon energies up to about 0.5 keV (refs 1, 2). This is achieved by focusing a femtosecond laser into a gas, and high harmonics of the fundamental laser frequency are radiated in the forward direction. However, although this process can generate high-energy photons, efficient high-harmonic generation has been demonstrated only for photon energies of the order 50-100 eV (ref. 5). Ionization of the gas prevents the laser and the EUV light from propagating at the same speed, which severely limits the conversion efficiency. Here we report a technique to overcome this problem, and demonstrate quasi-phase-matched frequency conversion of laser light into EUV. Using a modulated hollow-core waveguide to periodically vary the intensity of the laser light driving the conversion, we efficiently generate EUV light even in the presence of substantial ionization. The use of a modulated fibre shifts the energy spectrum of the high-harmonic light to significantly higher photon energies than would otherwise be possible. We expect that this technique could form the basis of coherent EUV sources for advanced lithography and high-resolution imaging applications. In future work, it might also be possible to generate isolated attosecond pulses.