Editors' Choice

Science  02 Mar 2007:
Vol. 315, Issue 5816, pp. 1194

    To Splice or Be Spliced?

    Spinal muscular atrophy (SMA) is an inherited disease characterized by the selective death of motor neurons, resulting in generalized muscle weakness that is often fatal in infancy or early childhood. SMA is caused by deletions or mutations in the gene encoding survival motor neuron 1 protein (SMN1), whose function is unclear. SMN1 contributes to the assembly of the pre-mRNA splicing machinery, and loss of SMN1 has been hypothesized to cause disease through disruption of mRNA splicing. However, this cannot readily explain the selective effect of SMN1 loss on motor neurons.

    An intriguing clue to this selectivity is provided by Setola et al., who identify a truncated form of SMN1 that arises from an alternative spliced SMN1 transcript that is preferentially expressed in the axonal projections of developing motor neurons. Forced expression of this SMN1 variant in cultured non-neuronal cells induces the formation of neurite-like extensions, a change in cell shape reminiscent of that occurring when motor neurons send out axons to their muscle targets. Whether this new variant of SMN1 affects axonal growth in vivo and plays a causal role in SMA remains to be investigated. — PAK

    Proc. Natl. Acad. Sci. U.S.A. 104, 1959 (2007).


    Diffusion Flashing into View

    Kinetic measurements with microsecond resolution have offered substantial insight into the folding mechanisms of proteins. However, before the folding event, protein chains undergo diffusional motion on a time scale of tens of nanoseconds that has proven challenging to probe. This time window is of particular interest because of its ready accessibility to theory. Nettels et al. have used single-molecule spectroscopy to resolve the nanosecond dynamics of unfolded cold-shock protein from Thermotoga maritima. They labeled the protein's ends with fluorophores and then detected changes in the chain geometries through shifts in the emitted photon statistics due to Förster resonance energy transfer. By comparing the resulting autocorrelation functions with model calculations, they could extract diffusion coefficients and reconfiguration times, which in turn contribute to a quantitative picture of the free-energy landscape. A significant (fivefold) decrease in the diffusion coefficient was observed on chain collapse, a pre-folded state induced by lowering the concentration of denaturant. — JSY

    Proc. Natl. Acad. Sci. U.S.A. 104, 2655 (2007).


    Superplume in Silico

    Rising beneath South Africa from the base of Earth's mantle is a giant plume of hot material: the African superplume. This feature has distinct edges and rises buoyantly like a plume of smoke from the core/mantle boundary, reaching a height of 1500 km beneath the continent. Simmons et al. have constructed a theoretical model of the African superplume incorporating seismic observations, motions of the overlying tectonic plates, and the elongated shape of the core/mantle boundary, as well as detailed mineral physics. They find that temperature effects can reproduce most of the plume's properties, but there remain some anomalies that must be due instead to chemical differences. Notably, a denser material seems to lie in the mid-mantle region of the plume, 1000 km above the core/mantle boundary, which is also the site where the temperature is highest. Thus, this density anomaly counteracts the density drop that the heat would naturally produce. This anomaly may be the remnant of a pile of dense material entrained from the superplume's base. — JB

    Geophys. Res. Lett. 33, 10.1029/2006GL028009 (2007).


    Reading Chromatin Signatures

    Regulated gene expression requires a highly choreographed assembly and disassembly of transcription factors to segments of DNA. This process must occur both near gene promoters and at enhancers, which can be present upstream or downstream of the gene being expressed. Specific epigenetic features also mark the degree of activity of the transcribing unit. Genes that are being actively transcribed generally contain nucleosomes with acetylated histone proteins, H3 and H4, as well as methylated H3; in contrast, DNA segments with inactive expression normally have deacetylated histones. Heintzman et al. used a combination of chromatin immunoprecipitation and microarray analysis to map histone modifications, transcription-factor binding, and nucleosome density within 30 Mb of the human genome. The study revealed that active human promoters were nucleosome-depleted. Furthermore, these promoters also showed enrichment of trimethylation of Lys4 of histone H3 (H3K4), whereas the enhancers showed enrichment of monomethylated H3K4.

    The authors went on to incorporate these distinct promoter and enhancer chromatin signatures into a computational algorithm. Analysis with this model allowed them to successfully predict the identities of several hundred promoters and enhancers of other genes in the 30-Mb region. — BAP

    Nat. Genet. 39, 10.1038/ng1966 (2007).


    Overturning Ocean Circulation

    It has been suggested that Atlantic meridional overturning circulation (MOC; the northward flow of water in the upper kilometer of the north Atlantic Ocean and southward flow below) could be affected by global warming, in turn substantially affecting the climate of the Northern Hemisphere, particularly in Europe. Observations of the strength of the circulation, taken over ∼1-month periods in different seasons of each of the years 1957, 1981, 1992, 1998, and 2004, have been used to argue that the MOC has slowed by about 30% over that interval. Searl et al. have now analyzed simulations of the MOC from the HadCM3 climate model and found no significant trend in the strength of the MOC over the period in question. Furthermore, variations in the MOC as large as 30% were very unusual.

    The discrepancy between the model and measurements may be due not to inherent limitations of the model, but rather to the small number of observations, short-term variability of the MOC, and measurement errors, which together inhibit accurate estimates of multidecadal trends from the data. Indeed, after taking all such factors into account, the HadCM3 results are fully consistent with the observations. To determine with confidence how the MOC may be changing on interannual and seasonal time scales in the warming world, continuous monitoring of water transport appears to be needed. — HJS

    Geophys. Res. Lett. 34, L03610 (2007).


    Cell Fate and Gametes

    Most eukaryotes, including plants, form female gametes or eggs. In Arabidopsis thaliana, the egg is formed from a haploid spore that undergoes multiple division cycles to create a structure known as a gametophyte that contains eight nuclei in four different cell types, including the egg. By examining egg-specific mutants, Gross-Hardt et al. were able to identify a gene, LACHESIS (LIS), that controls cell fate in egg development, independent of other gametophytic tissues. In heterozygote plants lacking one functional copy of LIS, 50% of the resulting gametophytes are malformed with multiple eggs, suggesting that LIS functions in the developmental specification of the egg. Furthermore, these eggs derive from a specific gametophytic cell type, the accessory cell, which forms next to the egg, potentially acting as a reserve in case of reproductive failure. LIS encodes a WD40 repeat protein homologous to a yeast splicing factor, which suggests that some aspects of cell fate may be controlled by the spliceosome. — LMZ

    PLoS Biol. 5 e47 (2007).

  7. STKE

    The Queen of Dopamine

    The queen bee controls the physiology and behavior of her fellow bees and essentially determines the workings of the entire society of insects. The queen exerts this influence by producing a cocktail of pheromones known as queen mandibular pheromone (QMP), but it has not been clear just how the mixture produces its effects. Beggs et al. noted that one component of QMP, homovanillyl alcohol (4-hydroxy-3-methoxyphenylethanol or HVA) has a chemical structure similar to that of the neurotransmitter dopamine. The authors therefore tested the effects of the pheromone on dopaminergic function in worker bees. Exposure of newly emerged adult bees to QMP for 2 days decreased the amount of mRNA transcript encoding one of the bee's dopamine receptors. Cultured neurons from the bees' mushroom body normally respond to dopamine with an increase in production of cAMP (adenosine 3′-5′monophosphate), but neurons taken from bees exposed to QMP showed a small decrease in the production of cAMP. HVA produced responses similar to those evoked by dopamine. Total amounts of dopamine in the brain were reduced in bees exposed to HVA for 2 days. Thus, the HVA in the QMP mixture may interact directly with dopamine receptors in the bee nervous system, perhaps decreasing the expression of dopamine receptors and thus altering the response of the neurons to endogenous dopamine. — LBR

    Proc. Natl. Acad. Sci. U.S.A. 104, 2460 (2007).