Cell biology: nondisjunction, aneuploidy and tetraploidy

One simple, widely accepted mechanism for generating an aberrant chromosome number, or aneuploidy, is through nondisjunction--a chromosome distribution error that occurs during mitosis when both copies of a duplicated chromosome are deposited into one daughter cell and none into the other. Shi and King challenge this view, concluding that nondisjunction does not yield aneuploid cells directly, but instead gives rise to tetraploid cells that may subsequently become aneuploid through further division. Here we show that the direct result of chromosome nondisjunction is gain or loss of a single chromosome, which results in near-diploid aneuploidy, not tetraploidy. We suggest that chromatin trapped in the cytokinetic cleavage furrow is the more likely reason for furrow regression and tetraploidization.     

ATM stabilizes DNA double-strand-break complexes during V(D)J recombination

The ATM (ataxia-telangiectasia mutated) protein kinase mediates early cellular responses to DNA double-strand breaks (DSBs) generated during metabolic processes or by DNA-damaging agents. ATM deficiency leads to ataxia-telangiectasia, a disease marked by lymphopenia, genomic instability and an increased predisposition to lymphoid malignancies with chromosomal translocations involving lymphocyte antigen receptor loci. ATM activates cell-cycle checkpoints and can induce apoptosis in response to DNA DSBs. However, defects in these pathways of the DNA damage response cannot fully account for the phenotypes of ATM deficiency. Here, we show that ATM also functions directly in the repair of chromosomal DNA DSBs by maintaining DNA ends in repair complexes generated during lymphocyte antigen receptor gene assembly. When coupled with the cell-cycle checkpoint and pro-apoptotic activities of ATM, these findings provide a molecular explanation for the increase in lymphoid tumours with translocations involving antigen receptor loci associated with ataxia-telangiectasia.     

Assessing the redundancy of MADS-box genes during carpel and ovule development

Carpels are essential for sexual plant reproduction because they house the ovules and subsequently develop into fruits that protect, nourish and ultimately disperse the seeds. The AGAMOUS (AG) gene is necessary for plant sexual reproduction because stamens and carpels are absent from ag mutant flowers. However, the fact that sepals are converted into carpelloid organs in certain mutant backgrounds even in the absence of AG activity indicates that an AG-independent carpel-development pathway exists. AG is a member of a monophyletic clade of MADS-box genes that includes SHATTERPROOF1 (SHP1), SHP2 and SEEDSTICK (STK), indicating that these four genes might share partly redundant activities. Here we show that the SHP genes are responsible for AG-independent carpel development. We also show that the STK gene is required for normal development of the funiculus, an umbilical-cord-like structure that connects the developing seed to the fruit, and for dispersal of the seeds when the fruit matures. We further show that all four members of the AG clade are required for specifying the identity of ovules, the landmark invention during the course of vascular plant evolution that enabled seed plants to become the most successful group of land plants.     

Melanopsin-expressing ganglion cells in primate retina signal colour and irradiance and project to the LGN

Human vision starts with the activation of rod photoreceptors in dim light and short (S)-, medium (M)-, and long (L)- wavelength-sensitive cone photoreceptors in daylight. Recently a parallel, non-rod, non-cone photoreceptive pathway, arising from a population of retinal ganglion cells, was discovered in nocturnal rodents. These ganglion cells express the putative photopigment melanopsin and by signalling gross changes in light intensity serve the subconscious, 'non-image-forming' functions of circadian photoentrainment and pupil constriction. Here we show an anatomically distinct population of 'giant', melanopsin-expressing ganglion cells in the primate retina that, in addition to being intrinsically photosensitive, are strongly activated by rods and cones, and display a rare, S-Off, (L + M)-On type of colour-opponent receptive field. The intrinsic, rod and (L + M) cone-derived light responses combine in these giant cells to signal irradiance over the full dynamic range of human vision. In accordance with cone-based colour opponency, the giant cells project to the lateral geniculate nucleus, the thalamic relay to primary visual cortex. Thus, in the diurnal trichromatic primate, 'non-image-forming' and conventional 'image-forming' retinal pathways are merged, and the melanopsin-based signal might contribute to conscious visual perception.     

Variability among five riparian cottonwood ( Populus fremontii Wats.) populations: an examination of size, density, and spatial distribution

Various abiotic and biotic factors are known to affect tree size, including age, genetics, and environment. Knowledge of size variation within natural riparian tree populations has both ecological and restorative importance. We determined tree sizes, basal area densities, and spatial distributions of 5 Populus fremontii Wats. populations within the Rio Grande watershed in New Mexico. At each site 10 randomly spaced plots, perpendicular to the river and extending from the river to the end of the forest, were established. Diameter at breast height (DBH) and distance to the river were determined for 1803 trees within the 5 populations, and stand cover (measured as basal area [BA] per hectare) was determined for each population. Significant variation in tree size and basal area density existed among sites. Mean DBH per site ranged from 11.7 to 58.4 cm and differed significantly ( P P 2 ha -1 . Spatial distribution of trees in relation to the river also differed among sites. Mean distance from the river ranged from 50 to 353 m and differed significantly ( P P. fremontii populations may be influenced by differences in water availability across a site; trees farthest from water sources may experience greater water stress and, therefore, growth limitation. Increasing BA cover with increasing tree size indicated no real thinning of mature trees within a population. Recruitment and establishment of cottonwood seedlings and saplings was evident only at sites with newly formed floodplains. For these 5 populations tree size appeared to be affected by environmental factors.     

Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers

Ovarian carcinomas with mutations in the tumour suppressor BRCA2 are particularly sensitive to platinum compounds. However, such carcinomas ultimately develop cisplatin resistance. The mechanism of that resistance is largely unknown. Here we show that acquired resistance to cisplatin can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. First, in a cisplatin-resistant BRCA2-mutated breast-cancer cell line, HCC1428, a secondary genetic change in BRCA2 rescued BRCA2 function. Second, cisplatin selection of a BRCA2-mutated pancreatic cancer cell line, Capan-1 (refs 3, 4), led to five different secondary mutations that restored the wild-type BRCA2 reading frame. All clones with secondary mutations were resistant both to cisplatin and to a poly(ADP-ribose) polymerase (PARP) inhibitor (AG14361). Finally, we evaluated recurrent cancers from patients whose primary BRCA2-mutated ovarian carcinomas were treated with cisplatin. The recurrent tumour that acquired cisplatin resistance had undergone reversion of its BRCA2 mutation. Our results suggest that secondary mutations that restore the wild-type BRCA2 reading frame may be a major clinical mediator of acquired resistance to platinum-based chemotherapy.     

A dynamical calibration of the mass-luminosity relation at very low stellar masses and young ages

Mass is the most fundamental parameter of a star, yet it is also one of the most difficult to measure directly. In general, astronomers estimate stellar masses by determining the luminosity and using the 'mass-luminosity' relationship, but this relationship has never been accurately calibrated for young, low-mass stars and brown dwarfs. Masses for these low-mass objects are therefore constrained only by theoretical models. A new high-contrast adaptive optics camera enabled the discovery of a young (50 million years) companion only 0.156 arcseconds (2.3 au) from the more luminous (> 120 times brighter) star AB Doradus A. Here we report a dynamical determination of the mass of the newly resolved low-mass companion AB Dor C, whose mass is 0.090 +/- 0.005 solar masses. Given its measured 1-2-micrometre luminosity, we have found that the standard mass-luminosity relations overestimate the near-infrared luminosity of such objects by about a factor of approximately 2.5 at young ages. The young, cool objects hitherto thought to be substellar in mass are therefore about twice as massive, which means that the frequency of brown dwarfs and planetary mass objects in young stellar clusters has been overestimated.     

The earliest evidence for anatomically modern humans in northwestern Europe

The earliest anatomically modern humans in Europe are thought to have appeared around 43,000-42,000 calendar years before present (43-42 kyr cal BP), by association with Aurignacian sites and lithic assemblages assumed to have been made by modern humans rather than by Neanderthals. However, the actual physical evidence for modern humans is extremely rare, and direct dates reach no farther back than about 41-39 kyr cal BP, leaving a gap. Here we show, using stratigraphic, chronological and archaeological data, that a fragment of human maxilla from the Kent's Cavern site, UK, dates to the earlier period. The maxilla (KC4), which was excavated in 1927, was initially diagnosed as Upper Palaeolithic modern human. In 1989, it was directly radiocarbon dated by accelerator mass spectrometry to 36.4-34.7 kyr cal BP. Using a Bayesian analysis of new ultrafiltered bone collagen dates in an ordered stratigraphic sequence at the site, we show that this date is a considerable underestimate. Instead, KC4 dates to 44.2-41.5 kyr cal BP. This makes it older than any other equivalently dated modern human specimen and directly contemporary with the latest European Neanderthals, thus making its taxonomic attribution crucial. We also show that in 13 dental traits KC4 possesses modern human rather than Neanderthal characteristics; three other traits show Neanderthal affinities and a further seven are ambiguous. KC4 therefore represents the oldest known anatomically modern human fossil in northwestern Europe, fills a key gap between the earliest dated Aurignacian remains and the earliest human skeletal remains, and demonstrates the wide and rapid dispersal of early modern humans across Europe more than 40 kyr ago.     

Sugar transporters for intercellular exchange and nutrition of pathogens

Sugar efflux transporters are essential for the maintenance of animal blood glucose levels, plant nectar production, and plant seed and pollen development. Despite broad biological importance, the identity of sugar efflux transporters has remained elusive. Using optical glucose sensors, we identified a new class of sugar transporters, named SWEETs, and show that at least six out of seventeen Arabidopsis, two out of over twenty rice and two out of seven homologues in Caenorhabditis elegans, and the single copy human protein, mediate glucose transport. Arabidopsis SWEET8 is essential for pollen viability, and the rice homologues SWEET11 and SWEET14 are specifically exploited by bacterial pathogens for virulence by means of direct binding of a bacterial effector to the SWEET promoter. Bacterial symbionts and fungal and bacterial pathogens induce the expression of different SWEET genes, indicating that the sugar efflux function of SWEET transporters is probably targeted by pathogens and symbionts for nutritional gain. The metazoan homologues may be involved in sugar efflux from intestinal, liver, epididymis and mammary cells.     

A conserved RNA-binding protein controls germline stem cells in Caenorhabditis elegans

Germline stem cells are defined by their unique ability to generate more of themselves as well as differentiated gametes. The molecular mechanisms controlling the decision between self-renewal and differentiation are central unsolved problems in developmental biology with potentially broad medical implications. In Caenorhabditis elegans, germline stem cells are controlled by the somatic distal tip cell. FBF-1 and FBF-2, two nearly identical proteins, which together are called FBF ('fem-3 mRNA binding factor'), were originally discovered as regulators of germline sex determination. Here we report that FBF also controls germline stem cells: in an fbf-1 fbf-2 double mutant, germline proliferation is initially normal, but stem cells are not maintained. We suggest that FBF controls germline stem cells, at least in part, by repressing gld-1, which itself promotes commitment to the meiotic cell cycle. FBF belongs to the PUF family ('Pumilio and FBF') of RNA-binding proteins. Pumilio controls germline stem cells in Drosophila females, and, in lower eukaryotes, PUF proteins promote continued mitoses. We suggest that regulation by PUF proteins may be an ancient and widespread mechanism for control of stem cells.