Phytohormone cytokinin guides microtubule dynamics during cell progression from proliferative to differentiated stage

Cell production and differentiation for the acquisition of specific functions are key features of living systems. The dynamic network of cellular microtubules provides the necessary platform to accommodate processes associated with the transition of cells through the individual phases of cytogenesis. Here, we show that the plant hormone cytokinin fine‐tunes the activity of the microtubular cytoskeleton during cell differentiation and counteracts microtubular rearrangements driven by the hormone auxin. The endogenous upward gradient of cytokinin activity along the longitudinal growth axis in Arabidopsis thaliana roots correlates with robust rearrangements of the microtubule cytoskeleton in epidermal cells progressing from the proliferative to the differentiation stage. Controlled increases in cytokinin activity result in premature re‐organization of the microtubule network from transversal to an oblique disposition in cells prior to their differentiation, whereas attenuated hormone perception delays cytoskeleton conversion into a configuration typical for differentiated cells. Intriguingly, cytokinin can interfere with microtubules also in animal cells, such as leukocytes, suggesting that a cytokinin‐sensitive control pathway for the microtubular cytoskeleton may be at least partially conserved between plant and animal cells

Somitogenesis Clock-Wave Initiation Requires Differential Decay and Multiple Binding Sites for Clock Protein

Somitogenesis is a process common to all vertebrate embryos in which repeated blocks of cells arise from the presomitic mesoderm (PSM) to lay a foundational pattern for trunk and tail development. Somites form in the wake of passing waves of periodic gene expression that originate in the tailbud and sweep posteriorly across the PSM. Previous work has suggested that the waves result from a spatiotemporally graded control protein that affects the oscillation rate of clock-gene expression. With a minimally constructed mathematical model, we study the contribution of two control mechanisms to the initial formation of this gene-expression wave. We test four biologically motivated model scenarios with either one or two clock protein transcription binding sites, and with or without differential decay rates for clock protein monomers and dimers. We examine the sensitivity of wave formation with respect to multiple model parameters and robustness to heterogeneity in cell population. We find that only a model with both multiple binding sites and differential decay rates is able to reproduce experimentally observed waveforms. Our results show that the experimentally observed characteristics of somitogenesis wave initiation constrain the underlying genetic control mechanisms

A Multi-cell, Multi-scale Model of Vertebrate Segmentation and Somite Formation

Somitogenesis, the formation of the body's primary segmental structure common to all vertebrate development, requires coordination between biological mechanisms at several scales. Explaining how these mechanisms interact across scales and how events are coordinated in space and time is necessary for a complete understanding of somitogenesis and its evolutionary flexibility. So far, mechanisms of somitogenesis have been studied independently. To test the consistency, integrability and combined explanatory power of current prevailing hypotheses, we built an integrated clock-and-wavefront model including submodels of the intracellular segmentation clock, intercellular segmentation-clock coupling via Delta/Notch signaling, an FGF8 determination front, delayed differentiation, clock-wavefront readout, and differential-cell-cell-adhesion-driven cell sorting. We identify inconsistencies between existing submodels and gaps in the current understanding of somitogenesis mechanisms, and propose novel submodels and extensions of existing submodels where necessary. For reasonable initial conditions, 2D simulations of our model robustly generate spatially and temporally regular somites, realistic dynamic morphologies and spontaneous emergence of anterior-traveling stripes of Lfng. We show that these traveling stripes are pseudo-waves rather than true propagating waves. Our model is flexible enough to generate interspecies-like variation in somite size in response to changes in the PSM growth rate and segmentation-clock period, and in the number and width of Lfng stripes in response to changes in the PSM growth rate, segmentation-clock period and PSM length

Effects of long-term exposure to an electronic containment system on the behaviour and welfare of domestic cats

Free-roaming cats are exposed to a variety of risks, including involvement in road traffic accidents. One way of mitigating these risks is to contain cats, for example using an electronic boundary fence system that delivers an electric ‘correction’ via a collar if a cat ignores a warning cue and attempts to cross the boundary. However, concerns have been expressed over the welfare impact of such systems. Our aim was to determine if long-term exposure to an electronic containment system was associated with reduced cat welfare. We compared 46 owned domestic cats: 23 cats that had been contained by an electronic containment system for more than 12 months (AF group); and 23 cats with no containment system that were able to roam more widely (C group). We assessed the cats’ behavioural responses and welfare via four behavioural tests (unfamiliar person test; novel object test; sudden noise test; cognitive bias test) and an owner questionnaire. In the unfamiliar person test, C group lip-licked more than the AF group, whilst the AF group looked at, explored and interacted more with the unfamiliar person than C group. In the novel object test, the AF group looked at and explored the object more than C group. No significant differences were found between AF and C groups for the sudden noise or cognitive bias tests. Regarding the questionnaire, C group owners thought their cats showed more irritable behaviour and AF owners thought that their cats toileted inappropriately more often than C owners. Overall, AF cats were less neophobic than C cats and there was no evidence of significant differences between the populations in general affective state. These findings indicate that an electronic boundary fence with clear pre-warning cues does not impair the long term quality of life of cat

Measures of Association for Identifying MicroRNA-mRNA Pairs of Biological Interest

MicroRNAs are a class of small non-protein coding RNAs that play an important role in the regulation of gene expression. Most studies on the identification of microRNA-mRNA pairs utilize the correlation coefficient as a measure of association. The use of correlation coefficient is appropriate if the expression data are available for several conditions and, for a given condition, both microRNA and mRNA expression profiles are obtained from the same set of individuals. However, there are many instances where one of the requirements is not satisfied. Therefore, there is a need for new measures of association to identify the microRNA-mRNA pairs of interest and we present two such measures. The first measure requires expression data for multiple conditions but, for a given condition, the microRNA and mRNA expression may be obtained from different individuals. The new measure, unlike the correlation coefficient, is suitable for analyzing large data sets which are obtained by combining several independent studies on microRNAs and mRNAs. Our second measure is able to handle expression data that correspond to just two conditions but, for a given condition, the microRNA and mRNA expression must be obtained from the same set of individuals. This measure, unlike the correlation coefficient, is appropriate for analyzing data sets with a small number of conditions. We apply our new measures of association to multiple myeloma data sets, which cannot be analyzed using the correlation coefficient, and identify several microRNA-mRNA pairs involved in apoptosis and cell proliferation

DNA copy number profiling reveals extensive genomic loss in hereditary BRCA1 and BRCA2 ovarian carcinomas

Background: Few studies have attempted to characterise genomic changes occurring in hereditary epithelial ovarian carcinomas (EOCs) and inconsistent results have been obtained. Given the relevance of DNA copy number alterations in ovarian oncogenesis and growing clinical implications of the BRCA-gene status, we aimed to characterise the genomic profiles of hereditary and sporadic ovarian tumours. Methods: High-resolution array Comparative Genomic Hybridisation profiling of 53 familial (21 BRCA1, 6 BRCA2 and 26 non- BRCA1/2) and 15 sporadic tumours in combination with supervised and unsupervised analysis was used to define common and/or specific copy number features. Results: Unsupervised hierarchical clustering did not stratify tumours according to their familial or sporadic condition or to their BRCA1/2 mutation status. Common recurrent changes, spanning genes potentially fundamental for ovarian carcinogenesis, regardless of BRCA mutations, and several candidate subtype-specific events were defined. Despite similarities, greater contribution of losses was revealed to be a hallmark of BRCA1 and BRCA2 tumours. Conclusion: Somatic alterations occurring in the development of familial EOCs do not differ substantially from the ones occurring in sporadic carcinomas. However, some specific features like extensive genomic loss observed in BRCA1/2 tumours may be of clinical relevance helping to identify BRCA-related patients likely to respond to PARP inhibitorsThis study was funded by the Fondo de Investigacio´n Sanitaria (FIS), Instituto de Salud Carlos III (grants CP07/00113 and PS09/01094

When Cytokinin, a Plant Hormone, Meets the Adenosine A2A Receptor: A Novel Neuroprotectant and Lead for Treating Neurodegenerative Disorders?

It is well known that cytokinins are a class of phytohormones that promote cell division in plant roots and shoots. However, their targets, biological functions, and implications in mammalian systems have rarely been examined. In this study, we show that one cytokinin, zeatin riboside, can prevent pheochromocytoma (PC12) cells from serum deprivation-induced apoptosis by acting on the adenosine A2A receptor (A2A-R), which was blocked by an A2A-R antagonist and a protein kinase A (PKA) inhibitor, demonstrating the functional ability of zeatin riboside by mediating through A2A-R signaling event. Since the A2A-R was implicated as a therapeutic target in treating Huntington’s disease (HD), a cellular model of HD was applied by transfecting mutant huntingtin in PC12 cells. By using filter retardation assay and confocal microscopy we found that zeatin riboside reversed mutant huntingtin (Htt)-induced protein aggregations and proteasome deactivation through A2A-R signaling. PKA inhibitor blocked zeatin riboside-induced suppression of mutant Htt aggregations. In addition, PKA activated proteasome activity and reduced mutant Htt protein aggregations. However, a proteasome inhibitor blocked both zeatin riboside-and PKA activator-mediated suppression of mutant Htt aggregations, confirming mediation of the A2A-R/PKA/proteasome pathway. Taken together, zeatin riboside might have therapeutic potential as a novel neuroprotectant and a lead for treating neurodegenerative disorders