Developmental biology: It takes muscle to make blood cells
Nature 512, 7514 (2014). doi:10.1038/nature13740
Authors: Suphansa Sawamiphak & Didier Y. R. Stainier
Blood stem cells derive at least in part from an embryonic vessel called the dorsal aorta. It emerges that a flanking tissue called the somite contributes cells and signals to this process. See Letters p.314 & p.319
Earth science: Warning signs of the Iquique earthquake
Nature 512, 7514 (2014). doi:10.1038/nature13655
Authors: Roland Bürgmann
An earthquake off Chile in 2014 occurred in a region where a great seismic event was expected. Two studies reveal that months of foreshocks and slow slip on the associated plate-boundary fault preceded the event. See Letters p.295 & p.299
Abrupt glacial climate shifts controlled by ice sheet changes
Nature 512, 7514 (2014). doi:10.1038/nature13592
Authors: Xu Zhang, Gerrit Lohmann, Gregor Knorr & Conor Purcell
During glacial periods of the Late Pleistocene, an abundance of proxy data demonstrates the existence of large and repeated millennial-scale warming episodes, known as Dansgaard–Oeschger (DO) events. This ubiquitous feature of rapid glacial climate change can be extended back as far as 800,000 years before present (bp) in the ice core record, and has drawn broad attention within the science and policy-making communities alike. Many studies have been dedicated to investigating the underlying causes of these changes, but no coherent mechanism has yet been identified. Here we show, by using a comprehensive fully coupled model, that gradual changes in the height of the Northern Hemisphere ice sheets (NHISs) can alter the coupled atmosphere–ocean system and cause rapid glacial climate shifts closely resembling DO events. The simulated global climate responses—including abrupt warming in the North Atlantic, a northward shift of the tropical rainbelts, and Southern Hemisphere cooling related to the bipolar seesaw—are generally consistent with empirical evidence. As a result of the coexistence of two glacial ocean circulation states at intermediate heights of the ice sheets, minor changes in the height of the NHISs and the amount of atmospheric CO2 can trigger the rapid climate transitions via a local positive atmosphere–ocean–sea-ice feedback in the North Atlantic. Our results, although based on a single model, thus provide a coherent concept for understanding the recorded millennial-scale variability and abrupt climate changes in the coupled atmosphere–ocean system, as well as their linkages to the volume of the intermediate ice sheets during glacials.
Continuing megathrust earthquake potential in Chile after the 2014 Iquique earthquake
Nature 512, 7514 (2014). doi:10.1038/nature13677
Authors: Gavin P. Hayes, Matthew W. Herman, William D. Barnhart, Kevin P. Furlong, Sebástian Riquelme, Harley M. Benz, Eric Bergman, Sergio Barrientos, Paul S. Earle & Sergey Samsonov
The seismic gap theory identifies regions of elevated hazard based on a lack of recent seismicity in comparison with other portions of a fault. It has successfully explained past earthquakes (see, for example, ref. 2) and is useful for qualitatively describing where large earthquakes might occur. A large earthquake had been expected in the subduction zone adjacent to northern Chile, which had not ruptured in a megathrust earthquake since a M ∼8.8 event in 1877. On 1 April 2014 a M 8.2 earthquake occurred within this seismic gap. Here we present an assessment of the seismotectonics of the March–April 2014 Iquique sequence, including analyses of earthquake relocations, moment tensors, finite fault models, moment deficit calculations and cumulative Coulomb stress transfer. This ensemble of information allows us to place the sequence within the context of regional seismicity and to identify areas of remaining and/or elevated hazard. Our results constrain the size and spatial extent of rupture, and indicate that this was not the earthquake that had been anticipated. Significant sections of the northern Chile subduction zone have not ruptured in almost 150 years, so it is likely that future megathrust earthquakes will occur to the south and potentially to the north of the 2014 Iquique sequence.
Gradual unlocking of plate boundary controlled initiation of the 2014 Iquique earthquake
Nature 512, 7514 (2014). doi:10.1038/nature13681
Authors: Bernd Schurr, Günter Asch, Sebastian Hainzl, Jonathan Bedford, Andreas Hoechner, Mauro Palo, Rongjiang Wang, Marcos Moreno, Mitja Bartsch, Yong Zhang, Onno Oncken, Frederik Tilmann, Torsten Dahm, Pia Victor, Sergio Barrientos & Jean-Pierre Vilotte
On 1 April 2014, Northern Chile was struck by a magnitude 8.1 earthquake following a protracted series of foreshocks. The Integrated Plate Boundary Observatory Chile monitored the entire sequence of events, providing unprecedented resolution of the build-up to the main event and its rupture evolution. Here we show that the Iquique earthquake broke a central fraction of the so-called northern Chile seismic gap, the last major segment of the South American plate boundary that had not ruptured in the past century. Since July 2013 three seismic clusters, each lasting a few weeks, hit this part of the plate boundary with earthquakes of increasing peak magnitudes. Starting with the second cluster, geodetic observations show surface displacements that can be associated with slip on the plate interface. These seismic clusters and their slip transients occupied a part of the plate interface that was transitional between a fully locked and a creeping portion. Leading up to this earthquake, the b value of the foreshocks gradually decreased during the years before the earthquake, reversing its trend a few days before the Iquique earthquake. The mainshock finally nucleated at the northern end of the foreshock area, which skirted a locked patch, and ruptured mainly downdip towards higher locking. Peak slip was attained immediately downdip of the foreshock region and at the margin of the locked patch. We conclude that gradual weakening of the central part of the seismic gap accentuated by the foreshock activity in a zone of intermediate seismic coupling was instrumental in causing final failure, distinguishing the Iquique earthquake from most great earthquakes. Finally, only one-third of the gap was broken and the remaining locked segments now pose a significant, increased seismic hazard with the potential to host an earthquake with a magnitude of >8.5.
Haematopoietic stem cell induction by somite-derived endothelial cells controlled by meox1
Haematopoietic stem cell induction by somite-derived endothelial cells controlled by meox1
Nature 512, 7514 (2014). doi:10.1038/nature13678
Authors: Phong Dang Nguyen, Georgina Elizabeth Hollway, Carmen Sonntag, Lee Barry Miles, Thomas Edward Hall, Silke Berger, Kristine Joy Fernandez, David Baruch Gurevich, Nicholas James Cole, Sara Alaei, Mirana Ramialison, Robert Lyndsay Sutherland, Jose Maria Polo, Graham John Lieschke & Peter David Currie
Haematopoietic stem cells (HSCs) are self-renewing stem cells capable of replenishing all blood lineages. In all vertebrate embryos that have been studied, definitive HSCs are generated initially within the dorsal aorta (DA) of the embryonic vasculature by a series of poorly understood inductive events. Previous studies have identified that signalling relayed from adjacent somites coordinates HSC induction, but the nature of this signal has remained elusive. Here we reveal that somite specification of HSCs occurs via the deployment of a specific endothelial precursor population, which arises within a sub-compartment of the zebrafish somite that we have defined as the endotome. Endothelial cells of the endotome are specified within the nascent somite by the activity of the homeobox gene meox1. Specified endotomal cells consequently migrate and colonize the DA, where they induce HSC formation through the deployment of chemokine signalling activated in these cells during endotome formation. Loss of meox1 activity expands the endotome at the expense of a second somitic cell type, the muscle precursors of the dermomyotomal equivalent in zebrafish, the external cell layer. The resulting increase in endotome-derived cells that migrate to colonize the DA generates a dramatic increase in chemokine-dependent HSC induction. This study reveals the molecular basis for a novel somite lineage restriction mechanism and defines a new paradigm in induction of definitive HSCs.
Jam1a–Jam2a interactions regulate haematopoietic stem cell fate through Notch signalling
Nature 512, 7514 (2014). doi:10.1038/nature13623
Authors: Isao Kobayashi, Jingjing Kobayashi-Sun, Albert D. Kim, Claire Pouget, Naonobu Fujita, Toshio Suda & David Traver
Notch signalling plays a key role in the generation of haematopoietic stem cells (HSCs) during vertebrate development and requires intimate contact between signal-emitting and signal-receiving cells, although little is known regarding when, where and how these intercellular events occur. We previously reported that the somitic Notch ligands, Dlc and Dld, are essential for HSC specification. It has remained unclear, however, how these somitic requirements are connected to the later emergence of HSCs from the dorsal aorta. Here we show in zebrafish that Notch signalling establishes HSC fate as their shared vascular precursors migrate across the ventral face of the somite and that junctional adhesion molecules (JAMs) mediate this required Notch signal transduction. HSC precursors express jam1a (also known as f11r) and migrate axially across the ventral somite, where Jam2a and the Notch ligands Dlc and Dld are expressed. Despite no alteration in the expression of Notch ligand or receptor genes, loss of function of jam1a led to loss of Notch signalling and loss of HSCs. Enforced activation of Notch in shared vascular precursors rescued HSCs in jam1a or jam2a deficient embryos. Together, these results indicate that Jam1a–Jam2a interactions facilitate the transduction of requisite Notch signals from the somite to the precursors of HSCs, and that these events occur well before formation of the dorsal aorta.
Interacting supernovae from photoionization-confined shells around red supergiant stars
Nature 512, 7514 (2014). doi:10.1038/nature13522
Authors: Jonathan Mackey, Shazrene Mohamed, Vasilii V. Gvaramadze, Rubina Kotak, Norbert Langer, Dominique M.-A. Meyer, Takashi J. Moriya & Hilding R. Neilson
Betelgeuse, a nearby red supergiant, is a fast-moving star with a powerful stellar wind that drives a bow shock into its surroundings. This picture has been challenged by the discovery of a dense and almost static shell that is three times closer to the star than the bow shock and has been decelerated by some external force. The two physically distinct structures cannot both be formed by the hydrodynamic interaction of the wind with the interstellar medium. Here we report that a model in which Betelgeuse’s wind is photoionized by radiation from external sources can explain the static shell without requiring a new understanding of the bow shock. Pressure from the photoionized wind generates a standing shock in the neutral part of the wind and forms an almost static, photoionization-confined shell. Other red supergiants should have much more massive shells than Betelgeuse, because the photoionization-confined shell traps up to 35 per cent of all mass lost during the red supergiant phase, confining this gas close to the star until it explodes. After the supernova explosion, massive shells dramatically affect the supernova light curve, providing a natural explanation for the many supernovae that have signatures of circumstellar interaction.
Inflammatory caspases are innate immune receptors for intracellular LPS
Nature 514, 7521 (2014). doi:10.1038/nature13683
Authors: Jianjin Shi, Yue Zhao, Yupeng Wang, Wenqing Gao, Jingjin Ding, Peng Li, Liyan Hu & Feng Shao
The murine caspase-11 non-canonical inflammasome responds to various bacterial infections. Caspase-11 activation-induced pyroptosis, in response to cytoplasmic lipopolysaccharide (LPS), is critical for endotoxic shock in mice. The mechanism underlying cytosolic LPS sensing and the responsible pattern recognition receptor are unknown. Here we show that human
Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes
Nature 514, 7521 (2014). doi:10.1038/nature13564
Authors: Xiaoting Wang, Naruhisa Ota, Paolo Manzanillo, Lance Kates, Jose Zavala-Solorio, Celine Eidenschenk, Juan Zhang, Justin Lesch, Wyne P. Lee, Jed Ross, Lauri Diehl, Nicholas van Bruggen, Ganesh Kolumam & Wenjun Ouyang
The connection between an altered gut microbiota and metabolic disorders such as obesity, diabetes, and cardiovascular disease is well established. Defects in preserving the integrity of the mucosal barriers can result in systemic endotoxaemia that contributes to chronic low-grade inflammation, which further promotes the development of metabolic syndrome. Interleukin (IL)-22 exerts essential roles in eliciting antimicrobial immunity and maintaining mucosal barrier integrity within the intestine. Here we investigate the connection between IL-22 and metabolic disorders. We find that the induction of IL-22 from innate lymphoid cells and CD4+ T cells is impaired in obese mice under various immune challenges, especially in the colon during infection with Citrobacter rodentium. While innate lymphoid cell populations are largely intact in obese mice, the upregulation of IL-23, a cytokine upstream of IL-22, is compromised during the infection. Consequently, these mice are susceptible to C. rodentium infection, and both exogenous IL-22 and IL-23 are able to restore the mucosal host defence. Importantly, we further unveil unexpected functions of IL-22 in regulating metabolism. Mice deficient in IL-22 receptor and fed with high-fat diet are prone to developing metabolic disorders. Strikingly, administration of exogenous IL-22 in genetically obese leptin-receptor-deficient (db/db) mice and mice fed with high-fat diet reverses many of the metabolic symptoms, including hyperglycaemia and insulin resistance. IL-22 shows diverse metabolic benefits, as it improves insulin sensitivity, preserves gut mucosal barrier and endocrine functions, decreases endotoxaemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. In summary, we identify the IL-22 pathway as a novel target for therapeutic intervention in metabolic diseases.
Inappropriate p53 activation during development induces features of CHARGE syndrome
Nature 514, 7521 (2014). doi:10.1038/nature13585
Authors: Jeanine L. Van Nostrand, Colleen A. Brady, Heiyoun Jung, Daniel R. Fuentes, Margaret M. Kozak, Thomas M. Johnson, Chieh-Yu Lin, Chien-Jung Lin, Donald L. Swiderski, Hannes Vogel, Jonathan A. Bernstein, Tania Attié-Bitach, Ching-Pin Chang, Joanna Wysocka, Donna M. Martin & Laura D. Attardi
CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and ear abnormalities. Despite 70–90% of CHARGE syndrome cases resulting from mutations in the gene CHD7, which encodes an ATP-dependent chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood. Surprisingly, our studies of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor protein p53 (p5325,26,53,54), along with a wild-type allele of p53 (also known as Trp53), revealed late-gestational embryonic lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer ear malformations, heart outflow tract defects and craniofacial defects. We found that the p5325,26,53,54 mutant protein stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, as p5325,26,53,54/− embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome.
Mechanism of Dis3l2 substrate recognition in the Lin28–let-7 pathway
Nature 514, 7521 (2014). doi:10.1038/nature13553
Authors: Christopher R. Faehnle, Jack Walleshauser & Leemor Joshua-Tor
The pluripotency factor Lin28 inhibits the biogenesis of the let-7 family of mammalian microRNAs. Lin28 is highly expressed in embryonic stem cells and has a fundamental role in regulation of development, glucose metabolism and tissue regeneration. Overexpression of Lin28 is correlated with the onset of numerous cancers, whereas let-7, a tumour suppressor, silences several human oncogenes. Lin28 binds to precursor let-7 (pre-let-7) hairpins, triggering the 3′ oligo-uridylation activity of TUT4 and TUT7 (refs 10, 11, 12). The oligoU tail added to pre-let-7 serves as a decay signal, as it is rapidly degraded by Dis3l2 (refs 13, 14), a homologue of the catalytic subunit of the RNA exosome. The molecular basis of Lin28-mediated recruitment of TUT4 and TUT7 to pre-let-7 and its subsequent degradation by Dis3l2 is largely unknown. To examine the mechanism of Dis3l2 substrate recognition we determined the structure of mouse Dis3l2 in complex with an oligoU RNA to mimic the uridylated tail of pre-let-7. Three RNA-binding domains form an open funnel on one face of the catalytic domain that allows RNA to navigate a path to the active site different from that of its exosome counterpart. The resulting path reveals an extensive network of uracil-specific interactions spanning the first 12 nucleotides of an oligoU-tailed RNA. We identify three U-specificity zones that explain how Dis3l2 recognizes, binds and processes uridylated pre-let-7 in the final step of the Lin28–let-7 pathway.
Required enhancer–matrin-3 network interactions for a homeodomain transcription program
Nature 514, 7521 (2014). doi:10.1038/nature13573
Authors: Dorota Skowronska-Krawczyk, Qi Ma, Michal Schwartz, Kathleen Scully, Wenbo Li, Zhijie Liu, Havilah Taylor, Jessica Tollkuhn, Kenneth A. Ohgi, Dimple Notani, Yoshinori Kohwi, Terumi Kohwi-Shigematsu & Michael G. Rosenfeld
Homeodomain proteins, described 30 years ago, exert essential roles in development as regulators of target gene expression; however, the molecular mechanisms underlying transcriptional activity of homeodomain factors remain poorly understood. Here investigation of a developmentally required POU-homeodomain transcription factor, Pit1 (also known as Pou1f1), has revealed that, unexpectedly, binding of Pit1-occupied enhancers to a nuclear matrin-3-rich network/architecture is a key event in effective activation of the Pit1-regulated enhancer/coding gene transcriptional program. Pit1 association with Satb1 (ref. 8) and β-catenin is required for this tethering event. A naturally occurring, dominant negative, point mutation in human PIT1(R271W), causing combined pituitary hormone deficiency, results in loss of Pit1 association with β-catenin and Satb1 and therefore the matrin-3-rich network, blocking Pit1-dependent enhancer/coding target gene activation. This defective activation can be rescued by artificial tethering of the mutant R271W Pit1 protein to the matrin-3 network, bypassing the pre-requisite association with β-catenin and Satb1 otherwise required. The matrin-3 network-tethered R271W Pit1 mutant, but not the untethered protein, restores Pit1-dependent activation of the enhancers and recruitment of co-activators, exemplified by p300, causing both enhancer RNA transcription and target gene activation. These studies have thus revealed an unanticipated homeodomain factor/β-catenin/Satb1-dependent localization of target gene regulatory enhancer regions to a subnuclear architectural structure that serves as an underlying mechanism by which an enhancer-bound homeodomain factor effectively activates developmental gene transcriptional programs.
X-ray structure of the mouse serotonin 5-HT3 receptor
Nature 512, 7514 (2014). doi:10.1038/nature13552
Authors: Ghérici Hassaine, Cédric Deluz, Luigino Grasso, Romain Wyss, Menno B. Tol, Ruud Hovius, Alexandra Graff, Henning Stahlberg, Takashi Tomizaki, Aline Desmyter, Christophe Moreau, Xiao-Dan Li, Frédéric Poitevin, Horst Vogel & Hugues Nury
Neurotransmitter-gated ion channels of the Cys-loop receptor family mediate fast neurotransmission throughout the nervous system. The molecular processes of neurotransmitter binding, subsequent opening of the ion channel and ion permeation remain poorly understood. Here we present the X-ray structure of a mammalian Cys-loop receptor, the
Retraction: Generation of pluripotent stem cells from adult human testis
Nature 512, 7514 (2014). doi:10.1038/nature13661
Authors: Sabine Conrad, Markus Renninger, Jörg Hennenlotter, Tina Wiesner, Lothar Just, Michael Bonin, Wilhelm Aicher, Hans-Jörg Bühring, Ulrich Mattheus, Andreas Mack, Hans-Joachim Wagner, Stephen Minger, Matthias Matzkies, Michael Reppel, Jürgen Hescheler, Karl-Dietrich Sievert, Arnulf Stenzl & Thomas Skutella
Nature456, 344–349 (2008); doi:10.1038/nature07404 Corrigendum Nature460, 1044 (2009); doi:10.1038/nature08353Brief Communication Arising Nature465, E1 (2010; doi: 10.1038/nature09089)The authors have provided new data to correct
Ribosomal frameshifting in the CCR5 mRNA is regulated by miRNAs and the NMD pathway
Nature 512, 7514 (2014). doi:10.1038/nature13429
Authors: Ashton Trey Belew, Arturas Meskauskas, Sharmishtha Musalgaonkar, Vivek M. Advani, Sergey O. Sulima, Wojciech K. Kasprzak, Bruce A. Shapiro & Jonathan D. Dinman
Programmed −1 ribosomal frameshift (−1 PRF) signals redirect translating ribosomes to slip back one base on messenger RNAs. Although well characterized in viruses, how these elements may regulate cellular gene expression is not understood. Here we describe a −1 PRF signal in the human mRNA
A vaccine targeting mutant IDH1 induces antitumour immunity
Nature 512, 7514 (2014). doi:10.1038/nature13387
Authors: Theresa Schumacher, Lukas Bunse, Stefan Pusch, Felix Sahm, Benedikt Wiestler, Jasmin Quandt, Oliver Menn, Matthias Osswald, Iris Oezen, Martina Ott, Melanie Keil, Jörg Balß, Katharina Rauschenbach, Agnieszka K. Grabowska, Isabel Vogler, Jan Diekmann, Nico Trautwein, Stefan B. Eichmüller, Jürgen Okun, Stefan Stevanović, Angelika B. Riemer, Ugur Sahin, Manuel A. Friese, Philipp Beckhove, Andreas von Deimling, Wolfgang Wick & Michael Platten
Monoallelic point mutations of isocitrate dehydrogenase type 1 (IDH1) are an early and defining event in the development of a subgroup of gliomas and other types of tumour. They almost uniformly occur in the critical arginine residue (Arg 132) in the catalytic pocket, resulting in a neomorphic enzymatic function, production of the oncometabolite 2-hydroxyglutarate (2-HG), genomic hypermethylation, genetic instability and malignant transformation. More than 70% of diffuse grade II and grade III gliomas carry the most frequent mutation, IDH1(R132H) (ref. 3). From an immunological perspective, IDH1(R132H) represents a potential target for immunotherapy as it is a tumour-specific potential neoantigen with high uniformity and penetrance expressed in all tumour cells. Here we demonstrate that IDH1(R132H) contains an immunogenic epitope suitable for mutation-specific vaccination. Peptides encompassing the mutated region are presented on major histocompatibility complexes (MHC) class II and induce mutation-specific CD4+ T-helper-1 (TH1) responses. CD4+ TH1 cells and antibodies spontaneously occurring in patients with IDH1(R132H)-mutated gliomas specifically recognize IDH1(R132H). Peptide vaccination of mice devoid of mouse MHC and transgenic for human MHC class I and II with IDH1(R132H) p123-142 results in an effective MHC class II-restricted mutation-specific antitumour immune response and control of pre-established syngeneic IDH1(R132H)-expressing tumours in a CD4+ T-cell-dependent manner. As IDH1(R132H) is present in all tumour cells of these slow-growing gliomas, a mutation-specific anti-IDH1(R132H) vaccine may represent a viable novel therapeutic strategy for IDH1(R132H)-mutated tumours.