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Karcz A.,University of Leipzig | Hennig M.H.,University of Edinburgh | Hennig M.H.,Center for Systems Biology at Edinburgh | Robbins C.A.,University of Washington | And 3 more authors.
Journal of Physiology | Year: 2011

Voltage-gated potassium (Kv) channels containing Kv1.1 subunits are strongly expressed in neurons that fire temporally precise action potentials (APs). In the auditory system, AP timing is used to localize sound sources by integrating interaural differences in time (ITD) and intensity (IID) using sound arriving at both cochleae. In mammals, the first nucleus to encode IIDs is the lateral superior olive (LSO), which integrates excitation from the ipsilateral ventral cochlear nucleus and contralateral inhibition mediated via the medial nucleus of the trapezoid body. Previously we reported that neurons in this pathway show reduced firing rates, longer latencies and increased jitter in Kv1.1 knockout (Kcna1-/-) mice. Here, we investigate whether these differences have direct impact on IID processing by LSO neurons. Single-unit recordings were made from LSO neurons of wild-type (Kcna1+/+) and from Kcna1-/- mice. IID functions were measured to evaluate genotype-specific changes in integrating excitatory and inhibitory inputs. In Kcna1+/+ mice, IID sensitivity ranged from +27 dB (excitatory ear more intense) to -20 dB (inhibitory ear more intense), thus covering the physiologically relevant range of IIDs. However, the distribution of IID functions in Kcna1-/- mice was skewed towards positive IIDs, favouring ipsilateral sound positions. Our computational model revealed that the reduced performance of IID encoding in the LSO of Kcna1-/- mice is mainly caused by a decrease in temporal fidelity along the inhibitory pathway. These results imply a fundamental role for Kv1.1 in temporal integration of excitation and inhibition during sound source localization. © 2011 The Authors. Journal compilation © 2011 The Physiological Society.

O'Neill J.S.,University of Cambridge | O'Neill J.S.,Center for Systems Biology at Edinburgh | Van Ooijen G.,Center for Systems Biology at Edinburgh | Le Bihan T.,Center for Systems Biology at Edinburgh | And 2 more authors.
Journal of Biological Rhythms | Year: 2011

To refine mathematical models of the transcriptional/translational feedback loop in the clockwork of Arabidopsis thaliana, the investigators sought to determine the affinity of the transcription factors LHY, CCA1, and CHE for their cognate DNA target sequences in vitro. Steady-state dissociation constants were observed to lie in the low nanomolar range. Furthermore, the data suggest that the LHY/CCA1 heterodimer binds more tightly than either homodimer and that DNA binding of these complexes is temperature compensated. Finally, it was found that LHY binding to the evening element in vitro is enhanced by both molecular crowding effects and by casein kinase 2-mediated phosphorylation. © 2011 SAGE Publications.

Pokhilko A.,University of Edinburgh | Ramos J.A.,Mendel Biotechnology | Holtan H.,Mendel Biotechnology | Maszle D.R.,Mendel Biotechnology | And 3 more authors.
Journal of Theoretical Biology | Year: 2011

The E3 ubiquitin ligase COP1 (CONSTITUTIVE PHOTOMORPHOGENIC1) plays a key role in the repression of the plant photomorphogenic development in darkness. In the presence of light, COP1 is inactivated by a mechanism which is not completely understood. This leads to accumulation of COP1's target transcription factors, which initiates photomorphogenesis, resulting in dramatic changes of the seedling's physiology.Here we use a mathematical model to explore the possible mechanism of COP1 modulation upon dark/light transition in Arabidopsis thaliana based upon data for two COP1 target proteins: HY5 and HFR1, which play critical roles in photomorphogenesis. The main reactions in our model are the inactivation of COP1 by a proposed photoreceptor-related inhibitor I and interactions between COP1 and a CUL4 (CULLIN4)-based ligase. For building and verification of the model, we used the available published and our new data on the kinetics of HY5 and HFR1 together with the data on COP1 abundance. HY5 has been shown to accumulate at a slower rate than HFR1. To describe the observed differences in the timecourses of the "slow" target HY5 and the "fast" target HFR1, we hypothesize a switch between the activities of COP1 and CUL4 ligases upon dark/light transition, with COP1 being active mostly in darkness and CUL4 in light. The model predicts a bi-phasic kinetics of COP1 activity upon the exposure of plants to light, with its restoration after the initial decline and the following slow depletion of the total COP1 content. CUL4 activity is predicted to increase in the presence of light. We propose that the ubiquitin ligase switch is important for the complex regulation of multiple transcription factors during plants development. In addition, this provides a new mechanism for sensing the duration of light period, which is important for seasonal changes in plant development. © 2010 Elsevier Ltd.

Wenden B.,University of Edinburgh | Kozma-Bognar L.,University of Edinburgh | Kozma-Bognar L.,Hungarian Academy of Sciences | Edwards K.D.,University of Edinburgh | And 5 more authors.
Plant Journal | Year: 2011

The circadian clock is a fundamental feature of eukaryotic gene regulation that is emerging as an exemplar genetic sub-network for systems biology. The circadian system in Arabidopsis plants is complex, in part due to its phototransduction pathways, which are themselves under circadian control. We therefore analysed two simpler experimental systems. Etiolated seedlings entrained by temperature cycles showed circadian rhythms in the expression of genes that are important for the clock mechanism, but only a restricted set of downstream target genes were rhythmic in microarray assays. Clock control of phototransduction pathways remained robust across a range of light inputs, despite the arrhythmic transcription of light-signalling genes. Circadian interactions with light signalling were then analysed using a single active photoreceptor. Phytochrome A (phyA) is expected to be the only active photoreceptor that can mediate far-red (FR) light input to the circadian clock. Surprisingly, rhythmic gene expression was profoundly altered under constant FR light, in a phyA-dependent manner, resulting in high expression of evening genes and low expression of morning genes. Dark intervals were required to allow high-amplitude rhythms across the transcriptome. Clock genes involved in this response were identified by mutant analysis, showing that the EARLY FLOWERING 4 gene is a likely target and mediator of the FR effects. Both experimental systems illustrate how profoundly the light input pathways affect the plant circadian clock, and provide strong experimental manipulations to understand critical steps in the plant clock mechanism. © 2011 Blackwell Publishing Ltd.

Chew Y.H.,University of Edinburgh | Halliday K.J.,University of Edinburgh | Halliday K.J.,Center for Systems Biology at Edinburgh
Current Opinion in Biotechnology | Year: 2011

Global concerns such as food security and climate change have highlighted an urgent need for improved crop yield. Breakthroughs in Arabidopsis research provide fresh application routes to achieve novel crop varieties that can withstand or avoid stresses imposed by a changing growth environment. This review features advances in CBF-stress signalling that expand opportunities to produce super hardy crops that can withstand multiple abiotic stresses. It examines molecular external coincidence mechanisms that avoid abiotic stresses by confining plant growth and reproduction to favourable times of the year. The potential value of mathematical modelling approaches is discussed in relation to improving crop-stress resistance or avoidance, and forecasting crop performance. © 2010.

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