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[
Curr Biol,
1998]
Recent work on the Caenorhabditis elegans
clr-1 gene shows that the receptor tyrosine phosphatase that it encodes negatively regulates a receptor tyrosine kinase related to mammalian fibroblast growth factor receptors. This opens up a promising system for investigating receptor tyrosine phosphatase function.
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Curr Opin Cell Biol,
1993]
By utilizing both genetics and physical manipulations, studies on invertebrate embryos have provided substantial information on how cell interactions influence cell fate during development. The picture emerging from these studies suggest that while there may be varied and intricate patterns of cell interactions during the development of different embryos, the signaling molecules that convey positional information across cell membranes have been highly conserved.
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Curr Opin Genet Dev,
2001]
Although the underlying mechanisms of ageing are not understood, it is known that the longevity of the nematode Caenorhabditis elegans is modulated by an insulin/IGF-signalling pathway. The focus now is on how this pathway is regulated, how it controls nematode ageing, and how this relates to the ageing process in higher animals.
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Nat Rev Mol Cell Biol,
2000]
Cargo molecules have to be included in carrier vesicles of different forms and sizes to be transported between organelles. During this process, a limited set of proteins, including the coat proteins COPI, COPII and clathrin, carries out a programmed set of sequential interactions that lead to the budding of vesicles. A general model to explain the formation of coated vesicles is starting to emerge but the picture is more complex than we had imagined.
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J Neurochem,
2016]
Abnormal tau accumulations were observed and documented in post-mortem brains of patients affected by Alzheimer's disease (AD) long before the identification of mutations in the Microtubule-associated protein tau (MAPT) gene, encoding the tau protein, in a different neurodegenerative disease called Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). The discovery of mutations in the MAPT gene associated with FTDP-17 highlighted that dysfunctions in tau alone are sufficient to cause neurodegeneration. Invertebrate models have been diligently utilized in investigating tauopathies, contributing to the understanding of cellular and molecular pathways involved in disease etiology. An important discovery came with the demonstration that over-expression of human tau in Drosophila leads to premature mortality and neuronal dysfunction including neurodegeneration, recapitulating some key neuropathological features of the human disease. The simplicity of handling invertebrate models combined with the availability of a diverse range of experimental resources make these models, in particular Drosophila a powerful invertebrate screening tool. Consequently, several large-scale screens have been performed using Drosophila, to identify modifiers of tau toxicity. The screens have revealed not only common cellular and molecular pathways, but in some instances the same modifier has been independently identified in two or more screens suggesting a possible role for these modifiers in regulating tau toxicity. The purpose of this review is to discuss the genetic modifier screens on tauopathies performed in Drosophila and C. elegans models, and to highlight the common cellular and molecular pathways that have emerged from these studies. Here, we summarize results of tau toxicity screens providing mechanistic insights into pathological alterations in tauopathies. Key pathways or modifiers that have been identified are associated with a broad range of processes including, but not limited to, phosphorylation, cytoskeleton organization, axonal transport, regulation of cellular proteostasis, transcription, RNA metabolism, cell cycle regulation, and apoptosis. We discuss the utility and application of invertebrate models in elucidating the cellular and molecular functions of novel and uncharacterized disease modifiers identified in large-scale screens as well as for investigating the function of genes identified as risk factors in genome-wide association studies from human patients in the post-genomic era. In this review, we combined and summarized several large-scale modifier screens performed in invertebrate models to identify modifiers of tau toxicity. A summary of the screens show that diverse cellular processes are implicated in the modification of tau toxicity. Kinases and phosphatases are the most predominant class of modifiers followed by components required for cellular proteostasis and axonal transport and cytoskeleton elements.
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[
Dev Dyn,
2006]
Development is the result of complex events, including cascades of transcriptional programs and numerous molecular interactions. Traditionally, research focus has been given to the characterization of individual mutants, regulators, or interactions. With the availability of complete genome sequences and high-throughput (HT) experimental techniques, probing development on a system level has become feasible. Pioneering work initiated in invertebrate model systems such as Caenorhabditis elegans has provided first drafts of catalogs of essential components, transcriptional regulatory diagrams and molecular interaction networks underlying developmental processes. Integrating these drafts approximates a system-level picture of development and provides local models for protein/gene functions. Here we summarize the progress toward elucidating developmental processes on a system level, including the applications of genomic technologies and computational analyses. We discuss C. elegans embryonic development in case studies to illustrate how various HT approaches can be integrated and how biological insights can be gained from these approaches. Developmental Dynamics 2006. (c) 2006 Wiley-Liss, Inc.
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[
Trends Genet,
2000]
Transcription repression mediated through histone deacetylase (HDAC) complexes is widespread, and mechanisms by which HDAC complexes act have been revealed by extensive studies in vitro and in cell culture. However, until recently, little has been known about the developmental roles of histone deacetylation. Mutants now exist for a number of members of the two major HDAC complexes (NuRD and SIN3) and some associated proteins. The emerging picture is that these complexes have specific functions in development, rather than being required for most cellular processes.
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Dev Cell,
2007]
The par genes were discovered in genetic screens for regulators of cytoplasmic partitioning in the early embryo of C. elegans, and encode six different proteins required for asymmetric cell division by the worm zygote. Some of the PAR proteins are localized asymmetrically and form physical complexes with one another. Strikingly, the PAR proteins have been found to regulate cell polarization in many different contexts in diverse animals, suggesting they form part of an ancient and fundamental mechanism for cell polarization. Although the picture of how the PAR proteins function remains incomplete, cell biology and biochemistry are beginning to explain how PAR proteins polarize cells.
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[
Trends Genet,
2015]
Research into chromosome structure and organization is an old field that has seen some fascinating progress in recent years. Modern molecular methods that can describe the shape of chromosomes have begun to revolutionize our understanding of genome organization and the mechanisms that regulate gene activity. A picture is beginning to emerge of chromatin loops representing a widespread organizing principle of the chromatin fiber and the proteins cohesin and CCCTC-binding factor (CTCF) as key players anchoring such chromatin loops. Here we review our current understanding of the features of CTCF- and cohesin-mediated genome organization and how their evolution may have helped to shape genome structure.
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J Endocrinol,
2006]
Modulation of insulin/IGF signaling in the nematode Caenorhabditis elegans is the central determinant of the endocrine control of stress response, diapause, and aging. Mutations in many genes that interfere with, or are controlled by, insulin signaling have been identified in the last decade by genetic analyses in the worm. Most of these genes have orthologs in vertebrate genomes, and their functional characterization has provided multiple hints about conserved mechanisms for the genetic influence on aging. The emerging picture is that insulin-like molecules, through the activity of the DAF-2/insulin/ IGF-I-like receptor, and the DAF-16/FKHRL1/FOXO transcription factor, control the ability of the organism to deal with oxidative stress, and interfere with metabolic programs that help to determine lifespan.