Rab5 is a signalling GTPase involved in actin remodelling by receptor tyrosine kinases

Rab5 is a small GTPase involved in the control of intracellular trafficking, both at the level of receptor endocytosis and endosomal dynamics. The finding that Rab5 can be activated by receptor tyrosine kinases (RTK) raised the question of whether it also participates in effector pathways emanating from these receptors. Here we show that Rab5 is indispensable for a form of RTK-induced actin remodelling, called circular ruffling. Three independent signals, originating from Rab5, phosphatidylinositol-3-OH kinase and Rac, respectively, are simultaneously required for the induction of circular ruffles. Rab5 signals to the actin cytoskeleton through RN-tre, a previously identified Rab5-specific GTPase-activating protein (GAP). Here we demonstrate that RN-tre has the dual function of Rab5-GAP and Rab5 effector. We also show that RN-tre is critical for macropinocytosis, a process previously connected to the formation of circular ruffles. Finally, RN-tre interacts with both F-actin and actinin-4, an F-actin bundling protein. We propose that RN-tre establishes a three-pronged connection with Rab5, F-actin and actinin-4. This may aid crosslinking of actin fibres into actin networks at the plasma membrane. Thus, we have shown that Rab5 is a signalling GTPase and have elucidated the major molecular elements of its downstream pathway.     

A complementary transposon tool kit for Drosophila melanogaster using P and piggyBac

With the availability of complete genome sequence for Drosophila melanogaster, one of the next strategic goals for fly researchers is a complete gene knockout collection. The P-element transposon, the workhorse of D. melanogaster molecular genetics, has a pronounced nonrandom insertion spectrum. It has been estimated that 87% saturation of the approximately 13,500-gene complement of D. melanogaster might require generating and analyzing up to 150,000 insertions. We describe specific improvements to the lepidopteran transposon piggyBac and the P element that enabled us to tag and disrupt genes in D. melanogaster more efficiently. We generated over 29,000 inserts resulting in 53% gene saturation and a more diverse collection of phenotypically stronger insertional alleles. We found that piggyBac has distinct global and local gene-tagging behavior from that of P elements. Notably, piggyBac excisions from the germ line are nearly always precise, piggyBac does not share chromosomal hotspots associated with P and piggyBac is more effective at gene disruption because it lacks the P bias for insertion in 5' regulatory sequences.     

Meteoric smoke fallout over the Holocene epoch revealed by iridium and platinum in Greenland ice

An iridium anomaly at the Cretaceous/Tertiary boundary layer has been attributed to an extraterrestrial body that struck the Earth some 65 million years ago. It has been suggested that, during this event, the carrier of iridium was probably a micrometre-sized silicate-enclosed aggregate or the nanophase material of the vaporized impactor. But the fate of platinum-group elements (such as iridium) that regularly enter the atmosphere via ablating meteoroids remains largely unknown. Here we report a record of iridium and platinum fluxes on a climatic-cycle timescale, back to 128,000 years ago, from a Greenland ice core. We find that unexpectedly constant fallout of extraterrestrial matter to Greenland occurred during the Holocene, whereas a greatly enhanced input of terrestrial iridium and platinum masked the cosmic flux in the dust-laden atmosphere of the last glacial age. We suggest that nanometre-sized meteoric smoke particles, formed from the recondensation of ablated meteoroids in the atmosphere at altitudes >70 kilometres, are transported into the winter polar vortices by the mesospheric meridional circulation and are preferentially deposited in the polar ice caps. This implies an average global fallout of 14 +/- 5 kilotons per year of meteoric smoke during the Holocene.     

Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2

Headache attacks and autonomic dysfunctions characterize migraine, a very common, disabling disorder with a prevalence of 12% in the general population of Western countries. About 20% of individuals affected with migraine experience aura, a visual or sensory-motor neurological dysfunction that usually precedes or accompanies the headache. Although the mode of transmission is controversial, population-based and twin studies have implicated genetic factors, especially in migraine with aura. Familial hemiplegic migraine is a hereditary form of migraine characterized by aura and some hemiparesis. Here we show that mutations in the gene ATP1A2 that encodes the alpha2 subunit of the Na+/K+ pump are associated with familial hemiplegic migraine type 2 (FHM2) linked to chromosome 1q23 (OMIM 602481). Functional data indicate that the putative pathogenetic mechanism is triggered by a loss of function of a single allele of ATP1A2. This is the first report associating mutations of Na+K+ pump subunits to genetic diseases.     

Notch1 functions as a tumor suppressor in mouse skin

Notch proteins are important in binary cell-fate decisions and inhibiting differentiation in many developmental systems, and aberrant Notch signaling is associated with tumorigenesis. The role of Notch signaling in mammalian skin is less well characterized and is mainly based on in vitro studies, which suggest that Notch signaling induces differentiation in mammalian skin. Conventional gene targeting is not applicable to establishing the role of Notch receptors or ligands in the skin because Notch1-/- embryos die during gestation. Therefore, we used a tissue-specific inducible gene-targeting approach to study the physiological role of the Notch1 receptor in the mouse epidermis and the corneal epithelium of adult mice. Unexpectedly, ablation of Notch1 results in epidermal and corneal hyperplasia followed by the development of skin tumors and facilitated chemical-induced skin carcinogenesis. Notch1 deficiency in skin and in primary keratinocytes results in increased and sustained expression of Gli2, causing the development of basal-cell carcinoma-like tumors. Furthermore, Notch1 inactivation in the epidermis results in derepressed beta-catenin signaling in cells that should normally undergo differentiation. Enhanced beta-catenin signaling can be reversed by re-introduction of a dominant active form of the Notch1 receptor. This leads to a reduction in the signaling-competent pool of beta-catenin, indicating that Notch1 can inhibit beta-catenin-mediated signaling. Our results indicate that Notch1 functions as a tumor-suppressor gene in mammalian skin.     

Behaviourally driven gene expression reveals song nuclei in hummingbird brain

Hummingbirds have developed a wealth of intriguing features, such as backwards flight, ultraviolet vision, extremely high metabolic rates, nocturnal hibernation, high brain-to-body size ratio and a remarkable species-specific diversity of vocalizations. Like humans, they have also developed the rare trait of vocal learning, this being the ability to acquire vocalizations through imitation rather than instinct. Here we show, using behaviourally driven gene expression in freely ranging tropical animals, that the forebrain of hummingbirds contains seven discrete structures that are active during singing, providing the first anatomical and functional demonstration of vocal nuclei in hummingbirds. These structures are strikingly similar to seven forebrain regions that are involved in vocal learning and production in songbirds and parrots--the only other avian orders known to be vocal learners. This similarity is surprising, as songbirds, parrots and hummingbirds are thought to have evolved vocal learning and associated brain structures independently, and it indicates that strong constraints may influence the evolution of forebrain vocal nuclei.     

New theories for new instruments: Fabrizio Mordente's proportional compass and the genesis of Giordano Bruno's atomist geometry

The aim of this article is to shed light on an understudied aspect of Giordano Bruno's intellectual biography, namely, his career as a mathematical practitioner. Early interpreters, especially, have criticized Bruno's mathematics for being “outdated” or too “concrete”. However, thanks to developments in the study of early modern mathematics and the rediscovery of Bruno's first mathematical writings (four dialogues on Fabrizio's Mordente proportional compass), we are in a position to better understand Bruno's mathematics. In particular, this article aims to reopen the question of whether Bruno anticipated the concept of infinitesimal quantity. It does so by providing an analysis of the dialogues on Mordente's compass and of the historical circumstances under which those dialogues were written.     

Ecological notes of the alien species Godiva quadricolor (Gastropoda: Nudibranchia) occurring in Faro Lake (Italy)

The first record from Sicily of the introduced facelinid nudibranch Godiva quadricolor allowed the detection of trophic relationships with the polycerid Polycera hedgpethi, another non-native nudibranch, and with two bryozoan species, namely the naturalized Cheilostomatida Bugula neritina and the cryptogenic Ctenostomatida Amathia verticillata. The settlement of both nudibranchs was presumably promoted by a trophic shift of P. hedgpethi from the natural prey B. neritina towards the largely available and not exploited A. verticillata. This short food web, without evident links with native fauna and having G. quadricolor as the top predator, is described. A DNA barcoding approach was used to confirm the identity of this facelinid species and to explore the possible genetic divergence occurring among the samples analysed.