Systematic analysis of genes required for synapse structure and function

Chemical synapses are complex structures that mediate rapid intercellular signalling in the nervous system. Proteomic studies suggest that several hundred proteins will be found at synaptic specializations. Here we describe a systematic screen to identify genes required for the function or development of Caenorhabditis elegans neuromuscular junctions. A total of 185 genes were identified in an RNA interference screen for decreased acetylcholine secretion; 132 of these genes had not previously been implicated in synaptic transmission. Functional profiles for these genes were determined by comparing secretion defects observed after RNA interference under a variety of conditions. Hierarchical clustering identified groups of functionally related genes, including those involved in the synaptic vesicle cycle, neuropeptide signalling and responsiveness to phorbol esters. Twenty-four genes encoded proteins that were localized to presynaptic specializations. Loss-of-function mutations in 12 genes caused defects in presynaptic structure.     

Extremely slow Drude relaxation of correlated electrons

The electrical conduction of metals is governed by how freely mobile electrons can move throughout the material. This movement is hampered by scattering with other electrons, as well as with impurities or thermal excitations (phonons). Experimentally, the scattering processes of single electrons are not observed, but rather the overall response of all mobile charge carriers within a sample. The ensemble dynamics can be described by the relaxation rates, which express how fast the system approaches equilibrium after an external perturbation. Here we measure the frequency-dependent microwave conductivity of the heavy-fermion metal UPd2Al3 (ref. 4), finding that it is accurately described by the prediction for a single relaxation rate (the so-called Drude response). This is notable, as UPd2Al3 has strong interactions among the electrons that might be expected to lead to more complex behaviour. Furthermore, the relaxation rate of just a few gigahertz is extremely low--this is several orders of magnitude below those of conventional metals (which are typically around 10 THz), and at least one order of magnitude lower than previous estimates for comparable metals. These observations are directly related to the high effective mass of the charge carriers in this material and reveal the dynamics of interacting electrons.     

Predation: Prey plumage adaptation against falcon attack

Several plumage types are found in feral pigeons (Columba livia), but one type imparts a clear survival advantage during attacks by the swiftest of all predators--the peregrine falcon (Falco peregrinus). Here we use quantitative field observations and experiments to demonstrate both the selective nature of the falcon's choice of prey and the effect of plumage coloration on the survival of feral pigeons. This plumage colour is an independently heritable trait that is likely to be an antipredator adaptation against high-speed attacks in open air space.     

Mutations in dynamin 2 cause dominant centronuclear myopathy

Autosomal dominant centronuclear myopathy is a rare congenital myopathy characterized by delayed motor milestones and muscular weakness. In 11 families affected by centronuclear myopathy, we identified recurrent and de novo missense mutations in the gene dynamin 2 (DNM2, 19p13.2), which encodes a protein involved in endocytosis and membrane trafficking, actin assembly and centrosome cohesion. The transfected mutants showed reduced labeling in the centrosome, suggesting that DNM2 mutations might cause centronuclear myopathy by interfering with centrosome function.     

Placental alpha(2)-adrenoceptors control vascular development at the interface between mother and embryo

A substantial percentage of human pregnancies are lost as spontaneous abortions after implantation. This is often caused by an inadequately developed placenta. Proper development of the placental vascular system is essential to nutrient and gas exchange between mother and developing embryo. Here we show that alpha(2)-adrenoceptors, which are activated by adrenaline and noradrenaline, are important regulators of placental structure and function. Mice with deletions in the genes encoding alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptors died between embryonic days 9.5 and 11.5 from a severe defect in yolk-sac and placenta development. In wildtype placentae, alpha(2)-adrenoceptors are abundantly expressed in giant cells, which secrete angiogenic factors to initiate development of the placental vascular labyrinth. In placentae deficient in alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptors, the density of fetal blood vessels in the labyrinth was markedly lower than normal, leading to death of the embryos as a result of reduced oxygen and nutrient supply. Basal phosphorylation of the extracellular signal regulated kinases ERK1 and ERK2 was also lower than normal, suggesting that activation of the mitogen-activated protein kinase (MAP kinase) pathway by alpha(2)-adrenoceptors is required for placenta and yolk-sac vascular development. Thus, alpha(2)-adrenoceptors are essential at the placental interface between mother and embryo to establish the circulatory system of the placenta and thus maintain pregnancy.     

TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2

The I kappa B kinase (IKK), consisting of the IKK1 and IKK2 catalytic subunits and the NEMO (also known as IKK gamma) regulatory subunit, phosphorylates I kappa B proteins, targeting them for degradation and thus inducing activation of NF-kappa B (reviewed in refs 1, 2). IKK2 and NEMO are necessary for NF-kappa B activation through pro-inflammatory signals. IKK1 seems to be dispensable for this function but controls epidermal differentiation independently of NF-kappa B. Previous studies suggested that NF-kappa B has a function in the growth regulation of epidermal keratinocytes. Mice lacking RelB or I kappa B alpha, as well as both mice and humans with heterozygous NEMO mutations, develop skin lesions. However, the function of NF-kappa B in the epidermis remains unclear. Here we used Cre/loxP-mediated gene targeting to investigate the function of IKK2 specifically in epidermal keratinocytes. IKK2 deficiency inhibits NF-kappa B activation, but does not lead to cell-autonomous hyperproliferation or impaired differentiation of keratinocytes. Mice with epidermis-specific deletion of IKK2 develop a severe inflammatory skin disease, which is caused by a tumour necrosis factor-mediated, alpha beta T-cell-independent inflammatory response that develops in the skin shortly after birth. Our results suggest that the critical function of IKK2-mediated NF-kappa B activity in epidermal keratinocytes is to regulate mechanisms that maintain the immune homeostasis of the skin.     

Thermal history of Mars inferred from orbital geochemistry of volcanic provinces

Reconstruction of the geological history of Mars has been the focus of considerable attention over the past four decades, with important discoveries being made about variations in surface conditions. However, despite a significant increase in the amount of data related to the morphology, mineralogy and chemistry of the martian surface, there is no clear global picture of how magmatism has evolved over time and how these changes relate to the internal workings and thermal evolution of the planet. Here we present geochemical data derived from the Gamma Ray Spectrometer on board NASA's Mars Odyssey spacecraft, focusing on twelve major volcanic provinces of variable age. Our analysis reveals clear trends in composition that are found to be consistent with varying degrees of melting of the martian mantle. There is evidence for thickening of the lithosphere (17-25?km?Gyr(-1)) associated with a decrease in mantle potential temperature over time (30-40?K?Gyr(-1)). Our inferred thermal history of Mars, unlike that of the Earth, is consistent with simple models of mantle convection.