Structure-function Analysis of the Axon Guidance Molecules Sidestep and Beaten Path Ia in Drosophila Melanogaster PDF Download
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Author: Caroline Daniela Stefanie Heymann
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Category :
Languages : en
Pages :
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Author: Caroline Daniela Stefanie Heymann
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Languages : en
Pages :
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Author: Jaqueline Kinold
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Category :
Languages : en
Pages :
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Author: Huidy Shu
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Category :
Languages : en
Pages : 336
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Author: Julie Hayner Simpson
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Category :
Languages : en
Pages : 422
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Author: Douglas McIntosh Fambrough
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Category :
Languages : en
Pages : 526
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Author: Haley Elizabeth Brown
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Category : Axons
Languages : en
Pages : 354
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Author: David J. Forsthoefel
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Category : Actin
Languages : en
Pages :
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Abstract: The Drosophila melanogaster embryo is an ideal system in which to study axon guidance, because of the relative simplicity of the nervous system and the evolutionary conservation of the molecules utilized during development. The Abelson cytoplasmic tyrosine kinase regulates actin cytoskeletal dynamics in Drosophila, mice, and humans. In Drosophila, Abl is expressed in the developing central and peripheral nervous systems (CNS and PNS). In a genetic screen for modifiers of the Abl mutant semilethality phenotype, we identified trio, a cytoplasmic guanine nucleotide exchange factor that is also expressed in the CNS and regulates actin dynamics through Rho GTPases. Mutations in Abl and trio interacted genetically, leading to dramatic disruption of axon pathways at the CNS midline. Building upon these initial observations, we analyzed interactions between Abl, trio, and the attractive Netrin receptor frazzled (fra)/Deleted-in-Colorectal-Cancer (DCC). In fra;Abl and fra;trio double mutants, few axons crossed the midline, similar to the phenotype in trio, Abl mutants. Furthermore, mutations in Abl and trio suppressed the inappropriate midline crossover phenotype in embryos expressing the chimeric Robo-Fra receptor, consistent with an in vivo role for these molecules as Fra effectors. Fra bound Abl and Trio in coimmunoprecipitation and GST pulldown experiments, and tyrosine phosphorylation of Fra and Trio was elevated in cultured cells overexpressing Abl. Mutations in enabled (ena), another Abl substrate, suppressed the loss-of-commissure phenotype in fra, Abl, and trio mutants, as well as the Robo-Fra receptor phenotype. Together, these results suggest that Abl and Trio are effectors for multiple attractive receptors at the CNS midline, and that Ena may function during both attractive and repulsive signaling. Finally, a functional analysis of the requirement for Trio's conserved domains has been initiated. In transgenic rescue and overexpression experiments, TrioGEF1 was required for axon guidance across the CNS midline, while TrioSH3 inhibited midline crossing. Coexpression experiments with the Robo-Fra receptor and assays in other tissues and cultured cells suggest that the conserved N-terminal domain, spectrin-like repeats, and GEF2 domain may modulate GEF1 signaling in specific contexts. Future experiments must elucidate the mechanistic details of cytoskeletal control by Trio and Fra.
Author: Hong Iris Wan
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Category :
Languages : en
Pages : 392
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Author: Ashley Palani Wright
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Category : Drosophila
Languages : en
Pages : 0
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Author: LaFreda Janae Howard
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Category : Nervous system
Languages : en
Pages : 286
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In animals with complex nervous systems such as mammals and insects, signaling pathways are responsible for guiding axons to their appropriate synaptic targets. Importantly, when this process is not successful during the development of an organism, outcomes include catastrophes such as human neurological diseases and disorders. It is vital to determine the underlying causes of such diseases by understanding the development of the nervous system. There are many pathways that have been identified to play a role in this, however, we lack an understanding of how these pathways can promote such diverse outcomes in different populations of neurons. These pathways include conserved ligand and receptor complexes that can either synergistically or antagonistically determine the fate of axons. Among these complexes include Slit and Robo, the first ligand and receptor complex to be identified in Drosophila. Previous studies show that disrupting this complex causes ectopic midline crossing of axons in a wide range of animals. Here, to analyze the structural foundation of the diverse activities of Robo2, I examine the relative contributions of its Ig domains by generating transgenic animals expressing variant proteins. I show that Ig domains are not individually required for protein stabilization and localization in vivo. I also use a cell overlay assay to examine the structural and functional importance of all domains of Drosophila Robo2. Deleting the Ig1, Ig5, and Fn2 domains of Robo2 reduce Slit binding in cultured Drosophila cells. The other domains of Robo2 are individually dispensable in Robo2's ability to bind to Slit in vitro.
