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Available from: Megan G Davey
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Loss of function mutations in the centrosomal protein TALPID3 (KIAA0586) cause a failure of primary cilia formation in animal models and are associated with defective Hedgehog signalling. It is unclear, however, if TALPID3 is required only for primary cilia formation or if it is essential for all ciliogenesis, including that of motile cilia in multiciliate cells.
FOXJ1, a key regulator of multiciliate cell fate, is expressed in the dorsal neuroectoderm of the chicken forebrain and hindbrain at stage 20HH, in areas that will give rise to choroid plexuses in both wt and talpid(3) embryos. Wt ependymal cells of the prosencephalic choroid plexuses subsequently transition from exhibiting single short cilia to multiple long motile cilia at 29HH (E8). Primary cilia and long motile cilia were only rarely observed on talpid(3) ependymal cells. Electron microscopy determined that talpid(3) ependymal cells do develop multiple centrosomes in accordance with FOXJ1 expression, but these fail to migrate to the apical surface of ependymal cells although axoneme formation was sometimes observed.
TALPID3, which normally localises to the proximal centrosome, is essential for centrosomal migration prior to ciliogenesis but is not directly required for de novo centriologenesis, multiciliated fate, or axoneme formation.
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ABSTRACT: Genetically engineered (GE) livestock have existed since the mid-1980s, and, since then, a range of methods for delivery of the transgene have been developed, each with advantages and limitations. In regards to the wealth of possible methods for the production of GE animals, two general approaches have emerged. Historically first, the direct manipulation of the zygote (including manipulation of germ cells) now comes in many flavours, from direct pronuclear injection of double-stranded DNA constructs to the use of vectors to deliver the transgene. The second approach utilises an in vitro stage where cells are engineered in culture before being introduced in some way to the developing embryo. The former suffers from lack of control of transgene integration, which can expose the transgene to position effects. The latter can be exploited through homologous recombination to engineer specific genetic loci; with somatic cell cloning being the most widely used method. Both approaches can now be combined with the exciting new editor technologies to enable precise genome editing which in some cases does not involve the incorporation of a transgene. For methods involving the zygote, the use of specific vectors can be of advantage, and the same can be true for the manipulation of cells; however, many delivery strategies are possible for this process. Overall, the drivers for delivery method development have revolved around efficiency and specificity. With regard to viral vectors, and possibly nonviral nanoparticle formulations in the future, spectacular increases in transgenesis rates can be achieved. With the most widely used vector, based on a lentivirus genome, in some cases all animals born from injected zygotes can be transgenic. In livestock, where gestation and breeding times are long, this dramatically reduces the time to proof-of-concept for a given project. In addition, these founder animals will carry different transgene copy-numbers, which is associated with different levels of transgene expression. This strategy can be exploited to quickly produce a large cohort of animals that enable modelling of the range of phenotype observed in a population for a given disease. In addition to the delivery of a transgene, such vectors can also be beneficial for the delivery of reagents that facilitate genome engineering, the most exciting of which are the genome editors. In this situation, either the editor and/or any DNA sequence to be incorporated can be efficiently delivered if not essential for broad uptake of this approach. It is likely that nonintegrating vectors will be desirable. In summary, viral vectors have a broad utility in facilitating the production of GE animals. In the future, nonviral nanoparticles may offer similar opportunities. Given the breadth of methodologies available and with the anticipated use of GE livestock in both agricultural and biomedical applications gaining momentum, we are entering an era of unparalleled opportunity in this area of animal biotechnology.
Available from: Colin Farquharson
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ABSTRACT: Linear bone growth is widely recognized to be adversely affected in children with chronic kidney disease (CKD) and other chronic inflammatory disorders. The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) pathway is anabolic to the skeleton and inflammatory cytokines compromise bone growth through a number of different mechanisms, which include interference with the systemic as well as the tissue-level GH/IGF-1 axis. Despite attempts to promote growth and control disease, there are an increasing number of reports of the persistence of poor growth in a substantial proportion of patients receiving rhGH and/or drugs that block cytokine action. Thus, there is an urgent need to consider better and alternative forms of therapy that are directed specifically at the mechanism of the insult which leads to abnormal bone health. Suppressor of cytokine signaling 2 (SOCS2) expression is increased in inflammatory conditions including CKD, and is a recognized inhibitor of GH signaling. Therefore, in this review, we will focus on the premise that SOCS2 signaling represents a critical pathway in growth plate chondrocytes through which pro-inflammatory cytokines alter both GH/IGF-1 signaling and cellular function.
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