Editors' Choice

Science  21 Dec 2007:
Vol. 318, Issue 5858, pp. 1835

    Learning to Sing

    1. Katrina L. Kelner

    For full expression, language depends on an interplay between cognitive and motor skills. For example, people with a rare genetic form of developmental verbal dyspraxia have difficulty learning and producing the intricate, coordinated series of muscle movements necessary for speech, a result of a mutation in a brain transcription factor called FOXP2. In songbirds, this same protein is found in a brain region—area X—that is essential for the acquisition of the birds' characteristic song, which they learn under the close tutelage of an adult bird.

    Haesler et al. tested whether a deficit in FoxP2 would also produce communication deficits in zebra finches. They injected into area X a lentivirus vector carrying RNA interference sequences from FoxP2, which reduced FoxP2 mRNA by 70%. After the 2-month tutoring period, the treated birds' songs—normally a stereotyped series of syllables that remains stable throughout adulthood—were missing syllables and contained inappropriately repeated segments (errors similar to those of humans with dyspraxia). Some of the sounds were also poor copies of their tutor's original. Thus, without sufficient FoxP2, normal developmental motor learning could not take place. The authors speculate that FoxP2 is necessary for structural and functional changes in area X neurons as birds learn their songs. — KK

    PLoS Biol. 5, e321 (2007).


    Fertile Ground for Cancer Proteins

    1. Paula A. Kiberstis

    Leukemia inhibitory factor (LIF) is a secreted glycoprotein first identified, as its name implies, as a regulator of leukemic cell differentiation. More recently, attention has focused on the role of this cytokine in the female reproductive tract. In mice, LIF is one of the few molecules known to be required for implantation of the blastocyst, or earlystage embryo, into the uterus. Thus, it has been hypothesized that drugs targeting LIF activity could (depending on their mode of action) be used either to enhance fertility by promoting implantation or as contraceptives that prevent implantation. Progress on the latter front is reported by White et al., who have developed a potent LIF antagonist that is completely effective in blocking blastocyst implantation when administered systemically to mice. Whether this antagonist—a chemically stabilized mutant version of LIF that binds to its receptor but does not trigger downstream signals—has similar activity in primates remains to be explored. In independent work, Hu et al. find that LIF expression in the mouse uterus is positively regulated at the transcriptional level by p53, an intensely studied tumor suppressor protein. Discovery of this link between LIF and p53 raises the possibility that cancer drugs designed to activate p53 might be useful tools for investigating the mechanisms underlying blastocyst implantation or as an alternative means of enhancing fertility. — PAK

    Proc. Natl. Acad. Sci. U.S.A. 104, 19357 (2007); Nature 450, 721 (2007).


    Still Potent

    1. Beverly A. Purnell

    By introducing defined transcription factors into mouse and human fibroblasts, stem cell researchers have demonstrated that differentiated cells can be reprogrammed to a pluripotent state, in which the resultant iPS (induced pluripotent stem) cells display properties similar to those of embryonic stem cells. This work holds great promise for therapy; however, a number of serious obstacles remain. For example, some reprogramming protocols involve the introduction of the c-Myc transcription factor, which has been shown to increase tumorigenicity in mice. Nakagawa et al. describe a modified method for generating mouse and human iPS cells without using c-Myc. This altered protocol shows greater specific induction to iPS cells, albeit at lower efficiency and at a slower rate than when c-Myc is added. — BAP

    Nat. Biotechnol. 10.1038/nbt1374 (2007).


    A Stringent Policy of Exclusion

    1. Guy Riddihough

    With 95 of its 115 exons subject to alternative mRNA splicing, the Down syndrome cell adhesion molecule (Dscam) gene in Drosophila surely deserves a place in the Guinness Book of Records, having the potential to form 38,016 protein variants. Remarkably, each Dscam isoform has the same overall structure, as the alternatively spliced exons form clusters, with only one exon from each cluster being included in the translated protein. Olson et al. have identified heterogeneous nuclear ribonucleoprotein hrp36 as a factor critical for the mutually exclusive splicing of the exon 6 cluster, which contains 48 distinct exons; in its absence, concatenated exon 6 variants are found in Dscam. Using a RIP-Chip assay, they show that hrp36 binds throughout the exon 6 cluster, where it prevents the binding of another class of splicing factors, the serine/arginine-rich (SR) proteins, which promote exon inclusion. The authors suggest that hrp36 masks selector sites located just 5′ of each exon variant, thus precluding SR binding, with the result that only one selector site can interact productively with the single docking site upstream of the entire exon 6 cluster. The mutually exclusive nature of the docking site-selector interaction then ensures that only one exon 6 variant is included in each Dscam mRNA. Intriguingly, hrp36 has no effect on splicing of the other variable exon clusters, indicating that another mechanism must determine their mutually exclusive splicing. — GR

    Nat. Struct. Mol. Biol. 14, 1134 (2007).


    Balancing Strength and Number

    1. Barbara R. Jasny

    Homeostasis, the ability to maintain a steady state in the face of stresses, is a fundamental part of life for cells and for organisms. Wilson et al. have analyzed homeostatic changes at the level of synaptic connections in hippocampal neurons seeded onto a microfabricated surface. Imprinting the surface with a template of squares of increasing sizes created a series of micrometer-scale islands hosting neurons at identical densities but with an increasing number of potential partners. As the number of neurons on a square increased, the number of synaptic connections increased, but, surprisingly, the functional activity of the neurons as a population (measured in voltage clamp and current clamp experiments) did not. This scaling was mediated by a change in the kinds of connections the neurons made. As network size increased, the proportion of connections between excitatory and inhibitory neurons increased; in other words, neurons made more weaker connections. Changes in neuronal connectivity occur as a consequence of development, aging, and disease (such as Alzheimer's disease and autism), and analyses of this kind may help us to understand the ability of the brain to respond to changes and the pathologies that occur when it cannot. — BJ

    J. Neurosci. 27, 13581 (2007).


    Flowing into Focus

    1. Marc S. Lavine

    Most small-scale fluid systems are dominated by laminar, or nonmixing, flow. Thus, directing particle motion in sorting applications has required either an external applied force, such as that generated by an electrical or magnetic field, or else the use of geometrically complex arrangements of pillars or posts. These methods become less effective as the flow rate of the system increases, and hence the attainable particle throughput is limited. Di Carlo et al. show that particle motion can alternatively be controlled by designing channels that induce additional inertial forces. Particles suspended in a flowing fluid are subject to both drag and lift forces, with the lift forces driving the particles away from the center of the fluid channel. Rectangular channels therefore exhibit a four-channel output stream. When the authors incorporated curvature into the channels, the particles were subjected to a rotational flow (termed Dean flow) caused by the fluid's inertia. In symmetric channels, the four output streams were reduced to two; asymmetric curvature confined the particles to a single stream. Faster flow rates increased these additional forces and so induced faster focusing of the particles. In a further twist, asymmetric particles were observed to show positional and rotational ordering. — MSL

    Proc. Natl. Acad. Sci. U.S.A. 104, 18892 (2007).


    Setting Serotonin Bait

    1. Phil Szuromi

    When small molecules are incorporated into self-assembled monolayers (SAMs) as targets for recognition by larger biomolecules, the tethers used to extend the targets from the surface can often interfere with the recognition process. Moreover, even at low loading, the surface molecules may not disperse but instead phase-separate into clusters, thus creating steric hindrance and increasing the chances of nonspecific binding. Shuster et al. present a strategy to overcome these drawbacks in a search to identify yet unknown binding partners for serotonin. First they prepared alkane thiol SAMs on gold that were terminated with oligomers of ethylene glycol. Carboxyl-terminated thiols with twice the number of ethylene glycol repeats were then bound to defect sites in the SAMs and covalently capped with serotonin. Quartz crystal microbalance studies showed that these monolayers preferentially bound serotonin antibodies over those raised against dopamine and were also resistant to binding of bovine serum albumin. — PDS

    Adv. Mater. 10.1002/adma.200700082 (2007).

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