CPEB: a life in translation

Nearly two decades ago, Xenopus oocytes were found to contain mRNAs harboring a small sequence in their 3' untranslated regions that control cytoplasmic polyadenylation and translational activation during development. This cytoplasmic polyadenylation element (CPE) is the binding platform for CPE-binding protein (CPEB), which promotes polyadenylation-induced translation. Since then, the biochemistry and biology of CPEB has grown rather substantially: mechanistically, CPEB nucleates a complex of factors that regulates poly(A) elongation through, of all things, a deadenylating enzyme; biologically, CPEB mediates many processes including germ-cell development, cell division and cellular senescence, and synaptic plasticity and learning and memory. These observations underscore the growing complexities of CPEB involvement in cell function.     

Reduced X-linked diversity in derived populations of house mice

Contrasting patterns of X-linked vs. autosomal diversity may be indicative of the mode of selection operating in natural populations. A number of observations have shown reduced X-linked (or Z-linked) diversity relative to autosomal diversity in various organisms, suggesting a large impact of genetic hitchhiking. However, the relative contribution of other forces such as population bottlenecks, variation in reproductive success of the two sexes, and differential introgression remains unclear. Here, we survey 13 loci, 6 X-linked and 7 autosomal, in natural populations of the house mouse (Mus musculus) subspecies complex. We studied seven populations of three different subspecies, the eastern house mouse M. musculus castaneus, the central house mouse M. m. musculus, and the western house mouse M. m. domesticus, including putatively ancestral and derived populations for each. All populations display lower diversity on the X chromosomes relative to autosomes, and this effect is most pronounced in derived populations. To assess the role of demography, we fit the demographic parameters that gave the highest likelihood of the data using coalescent simulations. We find that the reduction in X-linked diversity is too large to be explained by a simple demographic model in at least two of four derived populations. These observations are also not likely to be explained by differences in reproductive success between males and females. They are consistent with a greater impact of positive selection on the X chromosome, and this is supported by the observation of an elevated K(A) and elevated K(A)/K(S) ratios on the rodent X chromosome. A second contribution may be that the X chromosome less readily introgresses across subspecies boundaries.     

Identification of candidate genes for dyslexia susceptibility on chromosome 18

Background

Six independent studies have identified linkage to chromosome 18 for developmental dyslexia or general reading ability. Until now, no candidate genes have been identified to explain this linkage. Here, we set out to identify the gene(s) conferring susceptibility by a two stage strategy of linkage and association analysis.

Methodology/Principal Findings

Linkage analysis: 264 UK families and 155 US families each containing at least one child diagnosed with dyslexia were genotyped with a dense set of microsatellite markers on chromosome 18. Association analysis: Using a discovery sample of 187 UK families, nearly 3000 SNPs were genotyped across the chromosome 18 dyslexia susceptibility candidate region. Following association analysis, the top ranking SNPs were then genotyped in the remaining samples. The linkage analysis revealed a broad signal that spans approximately 40 Mb from 18p11.2 to 18q12.2. Following the association analysis and subsequent replication attempts, we observed consistent association with the same SNPs in three genes; melanocortin 5 receptor (MC5R), dymeclin (DYM) and neural precursor cell expressed, developmentally down-regulated 4-like (NEDD4L).

Conclusions

Along with already published biological evidence, MC5R, DYM and NEDD4L make attractive candidates for dyslexia susceptibility genes. However, further replication and functional studies are still required.     

Effects of Neuronal Activity on Inositol Phospholipid Metabolism in the Rat Autonomic Nervous System

The effect of nerve stimulation on inositol phospholipid hydrolysis in autonomic tissue was assessed by direct measurement of [3H]inositol phosphate production in ganglia that had been preincubated with [3H]inositol. Within minutes, stimulation of the preganglionic nerve increased the [3H]inositol phosphate content of the superior cervical sympathetic ganglion indicating increased hydrolysis of inositol phospholipids. This effect was blocked in a low Ca2+, high Mg2+ medium. It was also greatly reduced when nicotinic and muscarinic antagonists were present together in normal medium. However, neither the nicotinic antagonist nor the muscarinic antagonist alone appeared to be as effective as both in combination. In other experiments, stimulation of the vagus nerve caused dramatic increases in [3H]inositol phosphate in the nodose ganglion but did not increase [3H]inositol phosphate in the nerve itself. This effect was insensitive to the cholinergic antagonists. Thus, neuronal activity increased inositol phospholipid hydrolysis in a sympathetic ganglion rich in synapses, as well as in a sensory ganglion that contains few synapses. In the sympathetic ganglion, synaptic stimulation activated inositol phospholipid hydrolysis and this was primarily due to cholinergic transmission; both nicotinic and muscarinic pathways appeared to be involved.     

The prevalence of androstenone anosmia

It has been estimated that approximately 30% of the population is unable to detect the odor of androstenone. These estimates, however, were made using tests and criteria optimized for identifying detection. Such criteria favor Type II over Type I errors--that is, they are excellent at identifying true detectors at the cost of erroneously labeling some detectors as non-detectors. Because these criteria were used to identify non-detectors, it is possible that the rate of non-detection may have been overestimated. To test this we screened 55 subjects for non-detection employing previously used methods. This screen yielded nine putative non-detectors, a 16.3% putative non-detection rate. We then retested these putative non-detectors using a forced choice (yes-no) paradigm to obtain a precise measure of their sensitivity. We found that this group of putative non-detectors was significantly above chance at detecting androstenone (P < 0.001), despite very low self-confidence in their performance. Based on the results of the signal detection analysis in this sample, we estimate the rate of actual androstenone non-detection in young healthy adults is between 1.8 and 5.96%, which is significantly lower than previously estimated. This finding is significant considering the implications of specific anosmias on the understanding of odor discrimination.     

Recurrent networks of submucous neurons controlling intestinal secretion: a modeling study

Secretomotor neurons, immunoreactive for vasoactive intestinal peptide (VIP), are important in controlling chloride secretion in the small intestine. These neurons form functional synapses with other submucosal VIP neurons and transmit via slow excitatory postsynaptic potentials (EPSPs). Thus they form a recurrent network with positive feedback. Intrinsic sensory neurons within the submucosa are also likely to form recurrent networks with positive feedback, provide substantial output to VIP neurons, and receive input from VIP neurons. If positive feedback within recurrent networks is sufficiently large, then neurons in the network respond to even small stimuli by firing at their maximum possible rate, even after the stimulus is removed. However, it is not clear whether such a mechanism operates within the recurrent networks of submucous neurons. We investigated this question by performing computer simulations of realistic models of VIP and intrinsic sensory neuron networks. In the expected range of electrophysiological properties, we found that activity in the VIP neuron network decayed slowly after cessation of a stimulus, indicating that positive feedback is not strong enough to support the uncontrolled firing state. The addition of intrinsic sensory neurons produced a low stable firing rate consistent with the common finding that basal secretory activity is, in part, neurogenic. Changing electrophysiological properties enables these recurrent networks to support the uncontrolled firing state, which may have implications with hypersecretion in the presence of enterotoxins such as cholera-toxin.