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Chen D.,Beijing Institute of Technology | Norris D.,MRC Mammalian Genetics Unit | Ventikos Y.,University College London
Proceedings of the Institution of Mechanical Engineers, Part H: Journal of Engineering in Medicine | Year: 2014

Precise specification of left-right asymmetry is essential for patterning the internal organs of vertebrates. Within the embryonic node, posteriorly polarised cilia rotate, causing a leftward fluid flow (nodal flow) that establishes left-right asymmetry. The mechanism by which an embryo senses nodal flow remains uncertain. Existing hypotheses argue that either nodal flow carries morphogen(s) or lipid-bounded vesicles towards the left, thereby generating an asymmetric signal, and/or that mechano-sensory cilia sense this unidirectional flow, stimulating left-sided intracellular calcium signalling. To date, direct and definitive evidence supporting these hypotheses has been lacking. In this study, we conduct a multiscale study to simulate the nodal cilia and the fluidic environment, analysing left-right signal transmission. By employing computational simulation techniques and solving the relevant three-dimensional unsteady transport equations, we study the flow pattern produced by the rotation of active cilia. By importing dilute species and particles into the computational domain, we investigate the transport of morphogens and nodal vesicular parcels, respectively. Furthermore, by extending the analysis to include the solid mechanics of passive deformable cilia and the coupling of their structural behaviour with the emerging fluid mechanics, we study the response of passive cilia to the nodal flow. Our results reproduce the unidirectional nodal flow, allowing us to evaluate the plausibility of both chemo- and mechano-sensing hypotheses. The quantitative measurements of the flow rate, the molecular transport and distribution provide guidance regarding the necessary morphogen molecular weights to break signalling symmetry. The passive sensory ciliary deformation gives indications regarding the plausibility of this mechano-signalling mechanism. © IMechE 2014. Source

Chen D.,University of Oxford | Norris D.,MRC Mammalian Genetics Unit | Ventikos Y.,University of Oxford
Medical Engineering and Physics | Year: 2011

Left-right symmetry breaking in the mammalian embryo is believed to occur in a transient embryonic structure, the node: rotational motion of cilia within this structure creates a leftward flow of liquid that is the first asymmetric event observed. A hypothesis, often referred to as the "two-cilia" hypothesis, proposes that the node contains two kinds of primary cilia: motile cilia, driven by motor proteins, that rotate clockwise generating the leftward flow and passive cilia that act as mechano-sensors, reacting mechanically to the emerging flow. The exact mechanism that underlies the initial breaking of symmetry remains unclear, in spite of several studies that have attempted to elucidate the processes involved. In this paper, we present two computational models to (i) simulate the unidirectional flow induced by the active ciliary motion as well as their propulsion on the passive cilia and to (ii) investigate the protein activity that produces the active ciliary rotation-like movement. The models presented incorporate methodologies from computational fluid dynamics, deformable mesh computational techniques and fluid-structure interaction analysis. By solving the three-dimensional unsteady transport equations, with suitable boundary conditions, we confirm that the whirling motion of active cilia is capable of inducing the unidirectional flow and that the passive cilia are pushed by this flow towards the left with a visible deformation of 41.7% of the ciliary length on the tip, supporting the plausibility of the two-cilia hypothesis. Further, by applying finite element analysis and grid deformation techniques, we investigate the ciliary motion triggered by the activation of protein motors and propose a possible dynein activation pattern that is able to produce the clockwise rotation of embryonic cilia. © 2010 IPEM. Source

Brown S.D.M.,MRC Mammalian Genetics Unit | Moore M.W.,International Mouse Phenotyping Consortium
Mammalian Genome | Year: 2012

Determining the function of all mammalian genes remains a major challenge for the biomedical science community in the 21st century. The goal of the International Mouse Phenotyping Consortium (IMPC) over the next 10 years is to undertake broad-based phenotyping of 20,000 mouse genes, providing an unprecedented insight into mammalian gene function. This short article explores the drivers for large-scale mouse phenotyping and provides an overview of the aims and processes involved in IMPC mouse production and phenotyping. © Springer Science+Business Media, LLC 2012. Source

Joyce P.I.,MRC Mammalian Genetics Unit | Fratta P.,University College London | Fisher E.M.C.,University College London | Acevedo-Arozena A.,MRC Mammalian Genetics Unit
Mammalian Genome | Year: 2011

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with no cure. Breakthroughs in understanding ALS pathogenesis came with the discovery of dominant mutations in the superoxide dismutase 1 gene (SOD1) and other genes, including the gene encoding transactivating response element DNA binding protein-43 (TDP-43). This has led to the creation of animal models to further our understanding of the disease and identify a number of ALS-causing mechanisms, including mitochondrial dysfunction, protein misfolding and aggregation, oxidative damage, neuronal excitotoxicity, non-cell autonomous effects and neuroinflammation, axonal transport defects, neurotrophin depletion, effects from extracellular mutant SOD1, and aberrant RNA processing. Here we summarise the SOD1 and TDP-43 animal models created to date, report on recent findings supporting the potential mechanisms of ALS pathogenesis, and correlate this understanding with current developments in the clinic. © 2011 Springer Science+Business Media, LLC. Source

Davis H.,University of Oxford | Lewis A.,University of Oxford | Spencer-Dene B.,Cancer Research UK Research Institute | Tateossian H.,MRC Mammalian Genetics Unit | And 3 more authors.
Journal of Pathology | Year: 2011

FBXW7 is the substrate recognition component of a SCF-type E3 ubiquitin ligase. It has multiple targets such as Notch1, c-Jun, and cyclin E that function in critical developmental and signalling pathways. Mutations in FBXW7 are often found in many types of cancer. In most cases, these mutations do not inactivate the protein, but are mono-allelic missense changes at specific arginine resides involved in substrate binding. We have hypothesized that FBXW7 mutations are selected in cancers for reasons other than haploinsufficiency or full loss-of-function. Given that the existing mutant Fbxw7 mice carry null alleles, we created a mouse model carrying one of the commonly occurring point mutations (Fbxw7R482Q in the WD40 substrate recognition domain of Fbxw7. Mice heterozygous for this mutation apparently developed normally in utero, died perinatally due to a defect in lung development, and in some cases showed cleft palate and eyelid fusion defects. By comparison, Fbxw7 +/- mice were viable and developed normally. Fbxw7-/- animals died of vascular abnormalities at E10.5. We screened known FBXW7 targets for changes in the lungs of the Fbxw7R482Q/+ mice and found Tgif1 and Klf5 to be up-regulated. Fbxw7R482Q alleles are not functionally equivalent to heterozygous or homozygous null alleles, and we propose that they are selected in tumourigenesis because they cause a selective or partial loss of FBXW7 function. © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Source

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