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Conserved roles for cytoskeletal components in determining laterality.

ABSTRACT: Consistently-biased left-right (LR) patterning is required for the proper placement of organs including the heart and viscera. The LR axis is especially fascinating as an example of multi-scale pattern formation, since here chiral events at the subcellular level are integrated and amplified into asymmetric transcriptional cascades and ultimately into the anatomical patterning of the entire body. In contrast to the other two body axes, there is considerable controversy about the earliest mechanisms of embryonic laterality. Many molecular components of asymmetry have not been widely tested among phyla with diverse bodyplans, and it is unknown whether parallel (redundant) pathways may exist that could reverse abnormal asymmetry states at specific checkpoints in development. To address conservation of the early steps of LR patterning, we used the Xenopus laevis (frog) embryo to functionally test a number of protein targets known to direct asymmetry in plants, fruit fly, and rodent. Using the same reagents that randomize asymmetry in Arabidopsis, Drosophila, and mouse embryos, we show that manipulation of the microtubule and actin cytoskeleton immediately post-fertilization, but not later, results in laterality defects in Xenopus embryos. Moreover, we observed organ-specific randomization effects and a striking dissociation of organ situs from effects on the expression of left side control genes, which parallel data from Drosophila and mouse. Remarkably, some early manipulations that disrupt laterality of transcriptional asymmetry determinants can be subsequently "rescued" by the embryo, resulting in normal organ situs. These data reveal the existence of novel corrective mechanisms, demonstrate that asymmetric expression of Nodal is not a definitive marker of laterality, and suggest the existence of amplification pathways that connect early cytoskeletal processes to control of organ situs bypassing Nodal. Counter to alternative models of symmetry breaking during neurulation (via ciliary structures absent in many phyla), our data suggest a widely-conserved role for the cytoskeleton in regulating left-right axis formation immediately after fertilization of the egg. The novel mechanisms that rescue organ situs, even after incorrect expression of genes previously considered to be left-side master regulators, suggest LR patterning as a new context in which to explore multi-scale redundancy and integration of patterning from the subcellular structure to the entire bodyplan.

SUBMITTER: McDowell GS

PROVIDER: S-EPMC4792684 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Conserved roles for cytoskeletal components in determining laterality.

McDowell Gary S GS Lemire Joan M JM Paré Jean-Francois JF Cammarata Garrett G Lowery Laura Anne LA Levin Michael M

Integrative biology : quantitative biosciences from nano to macro 20160301 3

Consistently-biased left-right (LR) patterning is required for the proper placement of organs including the heart and viscera. The LR axis is especially fascinating as an example of multi-scale pattern formation, since here chiral events at the subcellular level are integrated and amplified into asymmetric transcriptional cascades and ultimately into the anatomical patterning of the entire body. In contrast to the other two body axes, there is considerable controversy about the earliest mechanis ...[more]

PMID: 26928161

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Project description:Appropriate determination of the epileptic focus and its laterality are important for the diagnosis of mesial temporal lobe epilepsy (MTLE). The aims of this study are to establish a specific oscillatory distribution and laterality of the oscillatory power in unilateral MTLE with frequency analysis of magnetoencephalography (MEG), and to confirm their potential to carry significant information for determining lateralization of the epileptic focus. Thirty-five patients with MTLE [left (LtMTLE), 16; right (RtMTLE), 19] and 102 healthy control volunteers (CTR) were enrolled. Cortical oscillatory powers were compared among the groups by contrasting the source images using a one-way ANOVA model for each frequency band. Further, to compare the lateralization of regional oscillatory powers between LtMTLEs and RtMTLEs, the laterality index (LI) was calculated for four brain regions (frontal, temporal, parietal, and occipital) in each frequency band, which were compared between patient groups (LtMTLE, RtMTLE, and CTR), and used for machine learning prediction of the groups with support vector machine (SVM) with linear kernel function. Significant oscillatory power differences between MTLE and CTR were found in certain areas. In the theta to high-frequency oscillation bands, there were marked increases in the parietal lobe, especially on the left side, in LtMTLE. In the theta, alpha, and high-gamma bands, there were marked increases in the parietal lobe, especially on the right side in RtMTLE. Compared with CTR, LIs were significantly higher in 24/28 regions in LtMTLE, but lower in 4/28 regions and higher in 10/28 regions in RtMTLE. LI at the temporal lobe in the theta band was significantly higher in LtMTLE and significantly lower in RtMTLE. Comparing LtMTLE and RtMTLE, there were significant LI differences in most regions and frequencies (21/28 regions). In all frequency bands, there were significant differences between LtMTLE and RtMTLE in the temporal and parietal lobes. The leave-one-out cross-validation of the linear-SVM showed the classification accuracy to be over 91%, where the model had high specificity over 96% and mild sensitivity ~68-75%. Using MEG frequency analysis, the characteristics of the oscillatory power distribution in the MTLE were demonstrated. Compared with CTR, LIs shifted to the side of the epileptic focus in the temporal lobe in the theta band. The machine learning approach also confirmed that LIs have significant predictive ability in the lateralization of the epileptic focus. These results provide useful additional information for determining the laterality of the focus.

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Conserved roles for cytoskeletal components in determining laterality.

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Conserved roles for cytoskeletal components in determining laterality.

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