In This Issue
FEATURE ARTICLE, DEVELOPMENTAL BIOLOGY
Cell identity driven by gene networks
The same genetic blueprint exists inside each cell of a multicellular organism, including the cells of the early embryo. Although individual genes are regulated according to instructions within the genome, the nature of the overall regulatory system—and how it relates to the specific biological processes of development—has been unclear. Previous research has shown that cell specification during development is likely regulated by a gene regulatory network (GRN): a network of genes encoding transcription factors and signaling molecules that govern where and when developmental genes are turned on and off. On the basis of genomewide surveys, Paola Oliveri et al. assembled a GRN for the developing sea urchin embryo. The authors describe a GRN that directs the specification of the skeletogenic micromere cell lineage, which gives rise to the embryo's skeleton. To test how well the proposed GRN represents the developmental process, the authors systematically identified and localized every regulatory gene expressed during sea urchin embryogenesis. The proposed GRN can explain all steps of cell specification for the micromere lineage, and Oliveri et al. suggest that GRNs could provide a coherent explanation for how embryonic cells develop their ultimate identities. — M.M.
Fourth cleavage sea urchin embryo.
Global regulatory logic for specification of an embryonic cell lineage” by Paola Oliveri, Qiang Tu, and Eric H. Davidson (see pages 5955–5962)
BIOCHEMISTRY
Targeting the fungus among us
The RNAs of eukaryotes contain scattered noncoding regions (introns) that must be clipped out, or spliced, to produce functional proteins. Although such regions are a near-universal feature of RNA, differences among the splicing mechanisms of pathogenic organisms may offer novel therapeutic targets. In the bread mold Neurospora crassa, the enzyme CYT-18 (mitochondrial tyrosyl-tRNA synthetase) aids in the splicing of a particular class of these introns, called group I introns. Paul Paukstelis and Alan Lambowitz analyzed genome sequences of fungi and found that enzymes related to CYT-18, which have molecular adaptations that confer group I splicing capability, are unique to a particular subphylum of fungi, the Pezizomycotina. After biochemically confirming group I intron splicing activity for the enzymes from several fungi in this subphylum—including a soil fungus, Aspergillus nidulans, and two human pathogens, Coccidioides posadasii and Histoplasma capsulatum—the authors identified conserved features of the proteins involved in this capability. In addition to revealing how this new function evolved in fungi, the authors suggest that this unique group I intron splicing activity could be a target for new antifungal drugs. — M.M.
CYT-18 protein binds group I intron (blue) and tRNATyr (violet).
Identification and evolution of fungal mitochondrial tyrosyl-tRNA synthetases with group I intron splicing activity” by Paul J. Paukstelis and Alan M. Lambowitz (see pages 6010–6015)
MICROBIOLOGY
Anthrax hijacks antiinflammatory response
Chun Kim et al. report that the signaling pathways employed by anthrax share several features with normal antiinflammatory response, including increased apoptosis and accelerated migration. Anthrax toxin comprises three proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF). EF is an adenylyl cyclase that increases the concentration of cyclic AMP (cAMP). Because increased cAMP is known to induce migratory behavior in certain cells, the authors sought an in vitro model with which to determine the role played by EF. They found that PA and EF are necessary components in generating motile macrophages. The authors analyzed whole-genome expression profiles of EF- and PA-treated macrophages and verified their results with quantitative PCR. Many of the up-regulated genes had promoters containing cAMP-responsive elements, which serve as binding sites for the transcription factor that is largely responsible for EF-triggered migration. Kim et al. also show that COX-2 and adenosine—endogenous antiinflammatory molecules that activate cAMP signaling—have effects similar to EF on gene expression and macrophage migration. — K.M.
Macrophage exposed to anthrax edema toxin.
Antiinflammatory cAMP signaling and cell migration genes co-opted by the anthrax bacillus” by Chun Kim, Sarah Wilcox-Adelman, Yasuyo Sano, Wei-Jen Tang, R. John Collier, and Jin Mo Park (see pages 6150–6155)
NEUROSCIENCE, APPLIED MATHEMATICS
Cochlear spiral enhances low-frequency hearing
The unusual spiral shape of the cochlea improves low-frequency hearing in mammals and may account for nearly 70% of the variation in low-frequency hearing limits in mammals. The basilar membrane (BM) and its complement of sensory hair cells run the length of the cochlear spiral. The structure of the BM is graded, growing wider and thinner from the spiral's base to its apex and enabling the ear to detect high to low frequencies at different locations along the membrane. Daphne Manoussaki et al. report that the mammalian cochlea's spiral shape is responsible for concentrating the energy of sound waves near the outer edge of the BM, particularly near the far end of the cochlea (the apex), where the lowest frequency sounds are detected. The cochlear curvature gradient is a significant factor in low-frequency sensitivity and is linearly proportional to the log of the low-frequency hearing limit in mammals with generalist ears. Manoussaki et al. used ray-tracing software, behavioral data, and physical measurements of the cochlea to provide further evidence to support their previous theory that sound hugs the outer wall of the spiral ear canal. — K.M.
Three-dimensional reconstruction of a human inner ear.
The influence of cochlear shape on low-frequency hearing” by Daphne Manoussaki, Richard S. Chadwick, Darlene R. Ketten, Julie Arruda, Emilios K. Dimitriadis, and Jen T. O'Malley (see pages 6162–6166)
NEUROSCIENCE
Neuron hubs associated with epilepsy
When the brain's dentate gyrus (DG) is damaged, granule cells—which do not normally form synapses with each other—connect by means of mossy-fiber sprouting. Researchers believe that this increased connectivity may make the DG hyperexcitable and lead to seizures. Using a 50,000-neuron computer model of the DG, Robert Morgan and Ivan Soltesz altered the nature of granule cell connectivity and found that the formation of a number of highly connected “hubs” greatly increases DG excitability. The authors set up a control model that simulates moderate injury to the DG. They altered granule cell interconnectivity in several ways that seemed likely to accelerate excitation. Small, circular networks and “Hebbian-like” connectivity had no effect, but the introduction of a topology in which the number of synapses per neuron decays according to a power law increased total excitation. The authors suggest that the power law appears largely superfluous; all that is essential is that 5% of the granule cells are significantly more connected than the rest. This number lies at the low end of the range of granule cells with enlarged dendrites typically seen in injured DG, lending support to the theory that such cells are responsible for epilepsy. — K.M.
Schematic of a hub network.
Nonrandom connectivity of the epileptic dentate gyrus predicts a major role for neuronal hubs in seizures” by Robert J. Morgan and Ivan Soltesz (see pages 6179–6184)
