Evidence for a nuclear compartment of transcription and splicing located at chromosome domain boundaries

The nuclear topography of splicing snRNPs, mRNA transcripts and chromosome domains in various mammalian cell types are described. The visualization of splicing snRNPs, defined by the Sm antigen, and coiled bodies, revealed distinctly different distribution patterns in these cell types. Heat shock experiments confirmed that the distribution patterns also depend on physiological parameters. Using a combination of fluorescencein situ hybridization and immunodetection protocols, individual chromosome domains were visualized simultaneously with the Sm antigen or the transcript of an integrated human papilloma virus genome. Three-dimensional analysis of fluorescence-stained target regions was performed by confocal laser scanning microscopy. RNA transcripts and components of the splicing machinery were found to be generally excluded from the interior of the territories occupied by the individual chromosomes. Based on these findings we present a model for the functional compartmentalization of the cell nucleus. According to this model the space between chromosome domains, including the surface areas of these domains, defines a three-dimensional network-like compartment, termed the interchromosome domain (ICD) compartment, in which transcription and splicing of mRNA occurs

Morphological characterization of the AlphaA- and AlphaB-crystallin double knockout mouse lens

BACKGROUND: One approach to resolving some of the in vivo functions of alpha-crystallin is to generate animal models where one or both of the alpha-crystallin gene products have been eliminated. In the single alpha-crystallin knockout mice, the remaining alpha-crystallin may fully or partially compensate for some of the functions of the missing protein, especially in the lens, where both alphaA and alphaB are normally expressed at high levels. The purpose of this study was to characterize gross lenticular morphology in normal mice and mice with the targeted disruption of alphaA- and alphaB-crystallin genes (alphaA/BKO). METHODS: Lenses from 129SvEvTac mice and alphaA/BKO mice were examined by standard scanning electron microscopy and confocal microscopy methodologies. RESULTS: Equatorial and axial (sagittal) dimensions of lenses for alphaA/BKO mice were significantly smaller than age-matched wild type lenses. No posterior sutures or fiber cells extending to the posterior capsule of the lens were found in alphaA/BKO lenses. Ectopical nucleic acid staining was observed in the posterior subcapsular region of 5 wk and anterior subcapsular cortex of 54 wk alphaA/BKO lenses. Gross morphological differences were also observed in the equatorial/bow, posterior and anterior regions of lenses from alphaA/BKO mice as compared to wild mice. CONCLUSION: These results indicated that both alphaA- and alphaB-crystallin are necessary for proper fiber cell formation, and that the absence of alpha-crystallin can lead to cataract formation

Masked mRNA is stored with aggregated nuclear speckles and its asymmetric redistribution requires a homolog of mago nashi

<p>Abstract</p> <p>Background</p> <p>Many rapidly developing systems rely on the regulated translation of stored transcripts for the formation of new proteins essential for morphogenesis. The microspores of the water fern <it>Marsilea vestita </it>dehydrate as they mature. During this process both mRNA and proteins required for subsequent development are stored within the microspores as they become fully desiccated and enter into senescence. At this point microspores become transcriptionally silent and remain so upon rehydration and for the remainder of spermatogenesis. Transcriptional silencing coupled with the translation of preformed RNA makes the microspore of <it>M. vestita </it>a useful system in which to study post-transcriptional regulation of RNA.</p> <p>Results</p> <p>We have characterized the distribution of mRNA as well as several conserved markers of subnuclear bodies within the nuclei of desiccating spores. During this period, nuclear speckles containing RNA were seen to aggregate forming a single large coalescence. We found that aggregated speckles contain several masked mRNA species known to be essential for spermatogenesis. During spermatogenesis masked mRNA and associated speckle proteins were shown to fragment and asymmetrically localize to spermatogenous but not sterile cells. This asymmetric localization was disrupted by RNAi knockdown of the <it>Marsilea </it>homolog of the Exon Junction Complex core component Mago nashi.</p> <p>Conclusions</p> <p>A subset of masked mRNA is stored in association with nuclear speckles during the dormant phase of microspore development in <it>M. vestita</it>. The asymmetric distribution of specific mRNAs to spermatogenous but not sterile cells mirrors their translational activities and appears to require the EJC or EJC components. This suggests a novel role for nuclear speckles in the post-transcriptional regulation of transcripts.</p

A dynamical model reveals gene co-localizations in nucleus

Co-localization of networks of genes in the nucleus is thought to play an important role in determining gene expression patterns. Based upon experimental data, we built a dynamical model to test whether pure diffusion could account for the observed co-localization of genes within a defined subnuclear region. A simple standard Brownian motion model in two and three dimensions shows that preferential co-localization is possible for co-regulated genes without any direct interaction, and suggests the occurrence may be due to a limitation in the number of available transcription factors. Experimental data of chromatin movements demonstrates that fractional rather than standard Brownian motion is more appropriate to model gene mobilizations, and we tested our dynamical model against recent static experimental data, using a sub-diffusion process by which the genes tend to colocalize more easily. Moreover, in order to compare our model with recently obtained experimental data, we studied the association level between genes and factors, and presented data supporting the validation of this dynamic model. As further applications of our model, we applied it to test against more biological observations. We found that increasing transcription factor number, rather than factory number and nucleus size, might be the reason for decreasing gene co-localization. In the scenario of frequency-or amplitude-modulation of transcription factors, our model predicted that frequency-modulation may increase the co-localization between its targeted genes

A habituation account of change detection in same/different judgments

We investigated the basis of change detection in a short-term priming task. In two experiments, participants were asked to indicate whether or not a target word was the same as a previously presented cue. Data from an experiment measuring magnetoencephalography failed to find different patterns for “same” and “different” responses, consistent with the claim that both arise from a common neural source, with response magnitude defining the difference between immediate novelty versus familiarity. In a behavioral experiment, we tested and confirmed the predictions of a habituation account of these judgments by comparing conditions in which the target, the cue, or neither was primed by its presentation in the previous trial. As predicted, cue-primed trials had faster response times, and target-primed trials had slower response times relative to the neither-primed baseline. These results were obtained irrespective of response repetition and stimulus–response contingencies. The behavioral and brain activity data support the view that detection of change drives performance in these tasks and that the underlying mechanism is neuronal habituation

Genome-wide association study in 176,678 Europeans reveals genetic loci for tanning response to sun exposure.

The skin's tendency to sunburn rather than tan is a major risk factor for skin cancer. Here we report a large genome-wide association study of ease of skin tanning in 176,678 subjects of European ancestry. We identify significant association with tanning ability at 20 loci. We confirm previously identified associations at six of these loci, and report 14 novel loci, of which ten have never been associated with pigmentation-related phenotypes. Our results also suggest that variants at the AHR/AGR3 locus, previously associated with cutaneous malignant melanoma the underlying mechanism of which is poorly understood, might act on disease risk through modulation of tanning ability

On staying grounded and avoiding Quixotic dead ends

The 15 articles in this special issue on The Representation of Concepts illustrate the rich variety of theoretical positions and supporting research that characterize the area. Although much agreement exists among contributors, much disagreement exists as well, especially about the roles of grounding and abstraction in conceptual processing. I first review theoretical approaches raised in these articles that I believe are Quixotic dead ends, namely, approaches that are principled and inspired but likely to fail. In the process, I review various theories of amodal symbols, their distortions of grounded theories, and fallacies in the evidence used to support them. Incorporating further contributions across articles, I then sketch a theoretical approach that I believe is likely to be successful, which includes grounding, abstraction, flexibility, explaining classic conceptual phenomena, and making contact with real-world situations. This account further proposes that (1) a key element of grounding is neural reuse, (2) abstraction takes the forms of multimodal compression, distilled abstraction, and distributed linguistic representation (but not amodal symbols), and (3) flexible context-dependent representations are a hallmark of conceptual processing

fMR-adaptation indicates selectivity to audiovisual content congruency in distributed clusters in human superior temporal cortex

<p>Abstract</p> <p>Background</p> <p>Efficient multisensory integration is of vital importance for adequate interaction with the environment. In addition to basic binding cues like temporal and spatial coherence, meaningful multisensory information is also bound together by content-based associations. Many functional Magnetic Resonance Imaging (fMRI) studies propose the (posterior) superior temporal cortex (STC) as the key structure for integrating meaningful multisensory information. However, a still unanswered question is how superior temporal cortex encodes content-based associations, especially in light of inconsistent results from studies comparing brain activation to semantically matching (congruent) versus nonmatching (incongruent) multisensory inputs. Here, we used fMR-adaptation (fMR-A) in order to circumvent potential problems with standard fMRI approaches, including spatial averaging and amplitude saturation confounds. We presented repetitions of audiovisual stimuli (letter-speech sound pairs) and manipulated the associative relation between the auditory and visual inputs (congruent/incongruent pairs). We predicted that if multisensory neuronal populations exist in STC and encode audiovisual content relatedness, adaptation should be affected by the manipulated audiovisual relation.</p> <p>Results</p> <p>The results revealed an occipital-temporal network that adapted independently of the audiovisual relation. Interestingly, several smaller clusters distributed over superior temporal cortex within that network, adapted stronger to congruent than to incongruent audiovisual repetitions, indicating sensitivity to content congruency.</p> <p>Conclusions</p> <p>These results suggest that the revealed clusters contain multisensory neuronal populations that encode content relatedness by selectively responding to congruent audiovisual inputs, since unisensory neuronal populations are assumed to be insensitive to the audiovisual relation. These findings extend our previously revealed mechanism for the integration of letters and speech sounds and demonstrate that fMR-A is sensitive to multisensory congruency effects that may not be revealed in BOLD amplitude per se.</p