Bulletin of the American Physical Society
2008 APS March Meeting
Volume 53, Number 2
Monday–Friday, March 10–14, 2008; New Orleans, Louisiana
Session V7: Oscillations and Segmentation: Dynamical Genetic Regulation in Time and Space |
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Sponsoring Units: DBP GSNP Chair: Mogens Jensen, Niels Bohr Institute Room: Morial Convention Center RO5 |
Thursday, March 13, 2008 11:15AM - 11:51AM |
V7.00001: Building the Vertebrate Spine Invited Speaker: The vertebrate body can be subdivided along the antero-posterior (AP) axis into repeated structures called segments. This periodic pattern is established during embryogenesis by the somitogenesis process. Somites are generated in a rhythmic fashion from the paraxial mesoderm and subsequently differentiate to give rise to the vertebrae and skeletal muscles of the body. Somite formation involves an oscillator-the segmentation clock-whose periodic signal is converted into the periodic array of somite boundaries. This clock drives the dynamic expression of cyclic genes in the presomitic mesoderm and requires Notch and Wnt signaling. Microarray studies of the mouse presomitic mesoderm transcriptome reveal that the segmentation clock drives the periodic expression of a large network of cyclic genes involved in cell signaling. Mutually exclusive activation of the Notch/FGF and Wnt pathways during each cycle suggests that coordinated regulation of these three pathways underlies the clock oscillator. In humans, mutations in the genes associated to the function of this oscillator such as \textit{Dll3} or \textit{Lunatic Fringe} result in abnormal segmentation of the vertebral column such as those seen in congenital scoliosis. Whereas the segmentation clock is thought to set the pace of vertebrate segmentation, the translation of this pulsation into the reiterated arrangement of segment boundaries along the AP axis involves dynamic gradients of FGF and Wnt signaling. The FGF signaling gradient is established based on an unusual mechanism involving mRNA decay which provides an efficient means to couple the spatio-temporal activation of segmentation to the posterior elongation of the embryo. Another striking aspect of somite production is the strict bilateral symmetry of the process. Retinoic acid was shown to control aspects of this coordination by buffering destabilizing effects from the embryonic left-right machinery. Defects in this embryonic program controlling vertebral symmetry might lead to scoliosis in humans. Finally, the subsequent regional differentiation of the precursors of the vertebrae is controlled by \textit{Hox} genes, whose collinear expression controls both gastrulation of somite precursors and their subsequent patterning into region-specific types of structures. Therefore somite development provides an outstanding paradigm to study patterning and differentiation in vertebrate embryos. [Preview Abstract] |
Thursday, March 13, 2008 11:51AM - 12:27PM |
V7.00002: Modelling Ultradian Oscillations and Segmentation Invited Speaker: We model ultradian oscillations in four different eucaryotic systems: Hes1, p53-mdm2, NF-kB and Wnt-Notch. In each of the systems we identify the feed-back loops for the genetic regulations. Oscillations are possible when time delays are present, either by directly introducing a delay, by many steps in the loops or by saturated degradation. The oscillations are important for apoptosis and control of inflammation. The Wnt-Notch system is essential in embryo segmentation and we introduce a model in which the Wnt oscillates by itself but drives the Notch cycle out of phase with the Wnt cycle, in good agreement with experimental observations. [Preview Abstract] |
Thursday, March 13, 2008 12:27PM - 1:03PM |
V7.00003: Spatial Patterns of Recurved Sensory Organs in Drosophila Invited Speaker: The fruit fly Drosophila is one of the most intensely studied models of development. A subset of -nominally- identical cells on the anterior wing of Drosophila begins to differentiate at puparium formation, each developing a sensory organ. In wild type flies, every fifth cell becomes such a sensory organ. Recent studies on mutant flies have shown that the transcription factor Senseless and the micro RNA miR-9a play significant roles in the choice of bristle density and the regularity of their arrangement. We propose that this cell differentiation is due to a Turing-type bifurcation whereby periodic concentration gradients emerge spontaneously from a uniform background. A paradigmatic model with intra-cellular networks and lateral activation and inhibition between neighboring cells (for example, through the Notch signaling pathway) is shown to generate the observed arrangements of sensory organs. The theory makes several experimentally verifiable predictions. For example, we propose methods to create mutant flies with systematically increasing numbers of ectopic bristles. In our theory, post-transcriptional regulatory action of the micro RNA occurs through the choice of stable solutions of the network. [Preview Abstract] |
Thursday, March 13, 2008 1:03PM - 1:39PM |
V7.00004: Similarities and differences in the p53-mdm2 and NF-kB feedback loops Invited Speaker: Ultradian oscillations in the p53 and NF-kB signalling systems are produced using similar mechanisms: a negative feedback loop combined with an effective time delay. However, seemingly small differences in the molecular implementation of this mechanism mean that the NF-kB system is in equilibrium in the resting state, while the p53 system is far from equilibrium. I will discuss how this affects the dynamical response of the systems. In particular, I will argue that the nonequilibrium driving makes the p53 system respond much faster to external stimuli than the NF-kB system. The interesting question then is whether this makes sense physiologically, and is consistent with the fact that p53 triggers cell-cycle arrest and apoptosis, while NF-kB triggers the immune response. [Preview Abstract] |
Thursday, March 13, 2008 1:39PM - 2:15PM |
V7.00005: Dynamic Changes in microRNAs may Regulate Robustness of Wnt/Notch Signaling Invited Speaker: The mechanisms by which highly reproducible patterns are formed during embryonic development and organismal evolution despite stochasticity at the single cell level is one of the remaining mysteries in Biology. It has been proposed that a hidden layer of regulation formed through the interaction of microRNAs with protein coding gene networks maybe responsible. Recently developed next generation sequencing technologies afford an unprecedented opportunity to uncover novel aspects of miRNA function and evolution. We find extensive heterogeneity in sequences that correspond to mmu-let-7 (targets Wnt1) and mmu-miR-191 (targets Notch1). Approximately 20{\%} of let-7 and miR-191 have undergone modifications to increase stability and binding to the Wnt1 and Notch1 targets and are likely to be destroyed. In contrast, 80{\%} bind the targets with imperfect complementarity and lower stability and are likely to be sequestered and prevented from forming protein. We propose that these two species together form a highly fluid system that is able to absorb stochastic perturbations in gene expression. A gene that goes on to be translated into functional protein therefore must escape both buffers by significantly high expression. [Preview Abstract] |
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