A microRNA polycistron as a potential human oncogene

To date, more than 200 microRNAs have been described in humans; however, the precise functions of these regulatory, non-coding RNAs remains largely obscure. One cluster of microRNAs, the mir-17-92 polycistron, is located in a region of DNA that is amplified in human B-cell lymphomas. Here we compared B-cell lymphoma samples and cell lines to normal tissues, and found that the levels of the primary or mature microRNAs derived from the mir-17-92 locus are often substantially increased in these cancers. Enforced expression of the mir-17-92 cluster acted with c-myc expression to accelerate tumour development in a mouse B-cell lymphoma model. Tumours derived from haematopoietic stem cells expressing a subset of the mir-17-92 cluster and c-myc could be distinguished by an absence of apoptosis that was otherwise prevalent in c-myc-induced lymphomas. Together, these studies indicate that non-coding RNAs, specifically microRNAs, can modulate tumour formation, and implicate the mir-17-92 cluster as a potential human oncogene.     

An extant cichlid fish radiation emerged in an extinct Pleistocene lake

The haplochromine cichlid fish of the East African Great Lakes represent some of the fastest and most species-rich adaptive radiations known, but rivers in most of Africa accommodate only a few morphologically similar species of haplochromine cichlid fish. This has been explained by the wealth of ecological opportunity in large lakes compared with rivers. It is therefore surprising that the rivers of southern Africa harbour many, ecologically diverse haplochromines. Here we present genetic, morphological and biogeographical evidence suggesting that these riverine cichlids are products of a recent adaptive radiation in a large lake that dried up in the Holocene. Haplochromine species richness peaks steeply in an area for which geological data reveal the historical existence of Lake palaeo-Makgadikgadi. The centre of this extinct lake is now a saltpan north of the Kalahari Desert, but it once hosted a rapidly evolving fish species radiation, comparable in morphological diversity to that in the extant African Great Lakes. Importantly, this lake seeded all major river systems of southern Africa with ecologically diverse cichlids. This discovery reveals how local evolutionary processes operating during a short window of ecological opportunity can have a major and lasting effect on biodiversity on a continental scale.     

The first cleavage of the mouse zygote predicts the blastocyst axis

One of the unanswered questions in mammalian development is how the embryonic-abembryonic axis of the blastocyst is first established. It is possible that the first cleavage division contributes to this process, because in most mouse embryos the progeny of one two-cell blastomere primarily populate the embryonic part of the blastocyst and the progeny of its sister populate the abembryonic part. However, it is not known whether the embryonic-abembryonic axis is set up by the first cleavage itself, by polarity in the oocyte that then sets the first cleavage plane with respect to the animal pole, or indeed whether it can be divorced entirely from the first cleavage and established in relation to the animal pole. Here we test the importance of the orientation of the first cleavage by imposing an elongated shape on the zygote so that the division no longer passes close to the animal pole, marked by the second polar body. Non-invasive lineage tracing shows that even when the first cleavage occurs along the short axis imposed by this experimental treatment, the progeny of the resulting two-cell blastomeres tend to populate the respective embryonic and abembryonic parts of the blastocyst. Thus, the first cleavage contributes to breaking the symmetry of the embryo, generating blastomeres with different developmental characteristics.     

Evidence from the Mars Express High Resolution Stereo Camera for a frozen sea close to Mars' equator

It is thought that the Cerberus Fossae fissures on Mars were the source of both lava and water floods two to ten million years ago. Evidence for the resulting lava plains has been identified in eastern Elysium, but seas and lakes from these fissures and previous water flooding events were presumed to have evaporated and sublimed away. Here we present High Resolution Stereo Camera images from the European Space Agency Mars Express spacecraft that indicate that such lakes may still exist. We infer that the evidence is consistent with a frozen body of water, with surface pack-ice, around 5 degrees north latitude and 150 degrees east longitude in southern Elysium. The frozen lake measures about 800 x 900 km in lateral extent and may be up to 45 metres deep--similar in size and depth to the North Sea. From crater counts, we determined its age to be 5 +/- 2 million years old. If our interpretation is confirmed, this is a place that might preserve evidence of primitive life, if it has ever developed on Mars.     

Insights into microtubule nucleation from the crystal structure of human gamma-tubulin

Microtubules are hollow polymers of alphabeta-tubulin that show GTP-dependent assembly dynamics and comprise a critical part of the eukaryotic cytoskeleton. Initiation of new microtubules in vivo requires gamma-tubulin, organized as an oligomer within the 2.2-MDa gamma-tubulin ring complex (gamma-TuRC) of higher eukaryotes. Structural insight is lacking regarding gamma-tubulin, its oligomerization and how it promotes microtubule assembly. Here we report the 2.7-A crystal structure of human gamma-tubulin bound to GTP-gammaS (a non-hydrolysable GTP analogue). We observe a 'curved' conformation for gamma-tubulin-GTPgammaS, similar to that seen for GDP-bound, unpolymerized alphabeta-tubulin. Tubulins are thought to represent a distinct class of GTP-binding proteins, and conformational switching in gamma-tubulin might differ from the nucleotide-dependent switching of signalling GTPases. A crystal packing interaction replicates the lateral contacts between alpha- and beta-tubulins in the microtubule, and this association probably forms the basis for gamma-tubulin oligomerization within the gamma-TuRC. Laterally associated gamma-tubulins in the gamma-TuRC might promote microtubule nucleation by providing a template that enhances the intrinsically weak lateral interaction between alphabeta-tubulin heterodimers. Because they are dimeric, alphabeta-tubulins cannot form microtubule-like lateral associations in the curved conformation. The lateral array of gamma-tubulins we observe in the crystal reveals a unique functional property of a monomeric tubulin.     

Structural insights into mRNA recognition from a PIWI domain-siRNA guide complex

RNA interference and related RNA silencing phenomena use short antisense guide RNA molecules to repress the expression of target genes. Argonaute proteins, containing amino-terminal PAZ (for PIWI/Argonaute/Zwille) domains and carboxy-terminal PIWI domains, are core components of these mechanisms. Here we show the crystal structure of a Piwi protein from Archaeoglobus fulgidus (AfPiwi) in complex with a small interfering RNA (siRNA)-like duplex, which mimics the 5' end of a guide RNA strand bound to an overhanging target messenger RNA. The structure contains a highly conserved metal-binding site that anchors the 5' nucleotide of the guide RNA. The first base pair of the duplex is unwound, separating the 5' nucleotide of the guide from the complementary nucleotide on the target strand, which exits with the 3' overhang through a short channel. The remaining base-paired nucleotides assume an A-form helix, accommodated within a channel in the PIWI domain, which can be extended to place the scissile phosphate of the target strand adjacent to the putative slicer catalytic site. This study provides insights into mechanisms of target mRNA recognition and cleavage by an Argonaute-siRNA guide complex.