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Search Results: 1 - 10 of 85190 matches for " David Van Vactor "
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Drosophila Growth Cones Advance by Forward Translocation of the Neuronal Cytoskeletal Meshwork In Vivo
Douglas H. Roossien, Phillip Lamoureux, David Van Vactor, Kyle E. Miller
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0080136
Abstract: In vitro studies conducted in Aplysia and chick sensory neurons indicate that in addition to microtubule assembly, long microtubules in the C-domain of the growth cone move forward as a coherent bundle during axonal elongation. Nonetheless, whether this mode of microtubule translocation contributes to growth cone motility in vivo is unknown. To address this question, we turned to the model system Drosophila. Using docked mitochondria as fiduciary markers for the translocation of long microtubules, we first examined motion along the axon to test if the pattern of axonal elongation is conserved between Drosophila and other species in vitro. When Drosophila neurons were cultured on Drosophila extracellular matrix proteins collected from the Drosophila Kc167 cell line, docked mitochondria moved in a pattern indicative of bulk microtubule translocation, similar to that observed in chick sensory neurons grown on laminin. To investigate whether the C-domain is stationary or advances in vivo, we tracked the movement of mitochondria during elongation of the aCC motor neuron in stage 16 Drosophila embryos. We found docked mitochondria moved forward along the axon shaft and in the growth cone C-domain. This work confirms that the physical mechanism of growth cone advance is similar between Drosophila and vertebrate neurons and suggests forward translocation of the microtubule meshwork in the axon underlies the advance of the growth cone C-domain in vivo. These results highlight the need for incorporating en masse microtubule translocation, in addition to assembly, into models of axonal elongation.
Genetic and Functional Studies Implicate Synaptic Overgrowth and Ring Gland cAMP/PKA Signaling Defects in the Drosophila melanogaster Neurofibromatosis-1 Growth Deficiency
James A. Walker,Jean Y. Gouzi,Jennifer B. Long,Sidong Huang,Robert C. Maher,Hongjing Xia,Kheyal Khalil,Arjun Ray,David Van Vactor,René Bernards,André Bernards
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003958
Abstract: Neurofibromatosis type 1 (NF1), a genetic disease that affects 1 in 3,000, is caused by loss of a large evolutionary conserved protein that serves as a GTPase Activating Protein (GAP) for Ras. Among Drosophila melanogaster Nf1 (dNf1) null mutant phenotypes, learning/memory deficits and reduced overall growth resemble human NF1 symptoms. These and other dNf1 defects are relatively insensitive to manipulations that reduce Ras signaling strength but are suppressed by increasing signaling through the 3′-5′ cyclic adenosine monophosphate (cAMP) dependent Protein Kinase A (PKA) pathway, or phenocopied by inhibiting this pathway. However, whether dNf1 affects cAMP/PKA signaling directly or indirectly remains controversial. To shed light on this issue we screened 486 1st and 2nd chromosome deficiencies that uncover >80% of annotated genes for dominant modifiers of the dNf1 pupal size defect, identifying responsible genes in crosses with mutant alleles or by tissue-specific RNA interference (RNAi) knockdown. Validating the screen, identified suppressors include the previously implicated dAlk tyrosine kinase, its activating ligand jelly belly (jeb), two other genes involved in Ras/ERK signal transduction and several involved in cAMP/PKA signaling. Novel modifiers that implicate synaptic defects in the dNf1 growth deficiency include the intersectin-related synaptic scaffold protein Dap160 and the cholecystokinin receptor-related CCKLR-17D1 drosulfakinin receptor. Providing mechanistic clues, we show that dAlk, jeb and CCKLR-17D1 are among mutants that also suppress a recently identified dNf1 neuromuscular junction (NMJ) overgrowth phenotype and that manipulations that increase cAMP/PKA signaling in adipokinetic hormone (AKH)-producing cells at the base of the neuroendocrine ring gland restore the dNf1 growth deficiency. Finally, supporting our previous contention that ALK might be a therapeutic target in NF1, we report that human ALK is expressed in cells that give rise to NF1 tumors and that NF1 regulated ALK/RAS/ERK signaling appears conserved in man.
MicroRNA-Dependent Transcriptional Silencing of Transposable Elements in Drosophila Follicle Cells
Bruno Mugat?,Abdou Akkouche?,Vincent Serrano?,Claudia Armenise?,Blaise Li?,Christine Brun?,Tudor A. Fulga?,David Van Vactor,Alain Pélisson?,Séverine Chambeyron
PLOS Genetics , 2015, DOI: 10.1371/journal.pgen.1005194
Abstract: RNA interference-related silencing mechanisms concern very diverse and distinct biological processes, from gene regulation (via the microRNA pathway) to defense against molecular parasites (through the small interfering RNA and the Piwi-interacting RNA pathways). Small non-coding RNAs serve as specificity factors that guide effector proteins to ribonucleic acid targets via base-pairing interactions, to achieve transcriptional or post-transcriptional regulation. Because of the small sequence complementarity required for microRNA-dependent post-transcriptional regulation, thousands of microRNA (miRNA) putative targets have been annotated in Drosophila. In Drosophila somatic ovarian cells, genomic parasites, such as transposable elements (TEs), are transcriptionally repressed by chromatin changes induced by Piwi-interacting RNAs (piRNAs) that prevent them from invading the germinal genome. Here we show, for the first time, that a functional miRNA pathway is required for the piRNA-mediated transcriptional silencing of TEs in this tissue. Global miRNA depletion, caused by tissue- and stage-specific knock down of drosha (involved in miRNA biogenesis), AGO1 or gawky (both responsible for miRNA activity), resulted in loss of TE-derived piRNAs and chromatin-mediated transcriptional de-silencing of TEs. This specific TE de-repression was also observed upon individual titration (by expression of the complementary miRNA sponge) of two miRNAs (miR-14 and miR-34) as well as in a miR-14 loss-of-function mutant background. Interestingly, the miRNA defects differentially affected TE- and 3' UTR-derived piRNAs. To our knowledge, this is the first indication of possible differences in the biogenesis or stability of TE- and 3' UTR-derived piRNAs. This work is one of the examples of detectable phenotypes caused by loss of individual miRNAs in Drosophila and the first genetic evidence that miRNAs have a role in the maintenance of genome stability via piRNA-mediated TE repression.
Modeling Spinal Muscular Atrophy in Drosophila
Howard Chia-Hao Chang, Douglas N. Dimlich, Takakazu Yokokura, Ashim Mukherjee, Mark W. Kankel, Anindya Sen, Vasanthi Sridhar, Tudor A. Fulga, Anne C. Hart, David Van Vactor, Spyros Artavanis-Tsakonas
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003209
Abstract: Spinal Muscular Atrophy (SMA), a recessive hereditary neurodegenerative disease in humans, has been linked to mutations in the survival motor neuron (SMN) gene. SMA patients display early onset lethality coupled with motor neuron loss and skeletal muscle atrophy. We used Drosophila, which encodes a single SMN ortholog, survival motor neuron (Smn), to model SMA, since reduction of Smn function leads to defects that mimic the SMA pathology in humans. Here we show that a normal neuromuscular junction (NMJ) structure depends on SMN expression and that SMN concentrates in the post-synaptic NMJ regions. We conducted a screen for genetic modifiers of an Smn phenotype using the Exelixis collection of transposon-induced mutations, which affects approximately 50% of the Drosophila genome. This screen resulted in the recovery of 27 modifiers, thereby expanding the genetic circuitry of Smn to include several genes not previously known to be associated with this locus. Among the identified modifiers was wishful thinking (wit), a type II BMP receptor, which was shown to alter the Smn NMJ phenotype. Further characterization of two additional members of the BMP signaling pathway, Mothers against dpp (Mad) and Daughters against dpp (Dad), also modify the Smn NMJ phenotype. The NMJ defects caused by loss of Smn function can be ameliorated by increasing BMP signals, suggesting that increased BMP activity in SMA patients may help to alleviate symptoms of the disease. These results confirm that our genetic approach is likely to identify bona fide modulators of SMN activity, especially regarding its role at the neuromuscular junction, and as a consequence, may identify putative SMA therapeutic targets.
miR-132 Enhances Dendritic Morphogenesis, Spine Density, Synaptic Integration, and Survival of Newborn Olfactory Bulb Neurons
Manavendra Pathania, Juan Torres-Reveron, Lily Yan, Tomoki Kimura, Tiffany V. Lin, Valerie Gordon, Zhao-Qian Teng, Xinyu Zhao, Tudor A. Fulga, David Van Vactor, Angélique Bordey
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038174
Abstract: An array of signals regulating the early stages of postnatal subventricular zone (SVZ) neurogenesis has been identified, but much less is known regarding the molecules controlling late stages. Here, we investigated the function of the activity-dependent and morphogenic microRNA miR-132 on the synaptic integration and survival of olfactory bulb (OB) neurons born in the neonatal SVZ. In situ hybridization revealed that miR-132 expression occurs at the onset of synaptic integration in the OB. Using in vivo electroporation we found that sequestration of miR-132 using a sponge-based strategy led to a reduced dendritic complexity and spine density while overexpression had the opposite effects. These effects were mirrored with respective changes in the frequency of GABAergic and glutamatergic synaptic inputs reflecting altered synaptic integration. In addition, timely directed overexpression of miR-132 at the onset of synaptic integration using an inducible approach led to a significant increase in the survival of newborn neurons. These data suggest that miR-132 forms the basis of a structural plasticity program seen in SVZ-OB postnatal neurogenesis. miR-132 overexpression in transplanted neurons may thus hold promise for enhancing neuronal survival and improving the outcome of transplant therapies.
Conserved Genes Act as Modifiers of Invertebrate SMN Loss of Function Defects
Maria Dimitriadi equal contributor,James N. Sleigh equal contributor,Amy Walker equal contributor,Howard C. Chang,Anindya Sen,Geetika Kalloo,Jevede Harris,Tom Barsby,Melissa B. Walsh,John S. Satterlee,Chris Li,David Van Vactor,Spyros Artavanis-Tsakonas,Anne C. Hart
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1001172
Abstract: Spinal Muscular Atrophy (SMA) is caused by diminished function of the Survival of Motor Neuron (SMN) protein, but the molecular pathways critical for SMA pathology remain elusive. We have used genetic approaches in invertebrate models to identify conserved SMN loss of function modifier genes. Drosophila melanogaster and Caenorhabditis elegans each have a single gene encoding a protein orthologous to human SMN; diminished function of these invertebrate genes causes lethality and neuromuscular defects. To find genes that modulate SMN function defects across species, two approaches were used. First, a genome-wide RNAi screen for C. elegans SMN modifier genes was undertaken, yielding four genes. Second, we tested the conservation of modifier gene function across species; genes identified in one invertebrate model were tested for function in the other invertebrate model. Drosophila orthologs of two genes, which were identified originally in C. elegans, modified Drosophila SMN loss of function defects. C. elegans orthologs of twelve genes, which were originally identified in a previous Drosophila screen, modified C. elegans SMN loss of function defects. Bioinformatic analysis of the conserved, cross-species, modifier genes suggests that conserved cellular pathways, specifically endocytosis and mRNA regulation, act as critical genetic modifiers of SMN loss of function defects across species.
Fak56 functions downstream of integrin alphaPS3betanu and suppresses MAPK activation in neuromuscular junction growth
Pei-I Tsai, Hsiu-Hua Kao, Caroline Grabbe, Yu-Tao Lee, Aurnab Ghose, Tzu-Ting Lai, Kuan-Po Peng, David Van Vactor, Ruth H Palmer, Ruey-Hwa Chen, Shih-Rung Yeh, Cheng-Ting Chien
Neural Development , 2008, DOI: 10.1186/1749-8104-3-26
Abstract: We have generated mutants for the Drosophila FAK gene, Fak56. Null Fak56 mutants display overgrowth of larval neuromuscular junctions (NMJs). Localization of phospho-FAK and rescue experiments suggest that Fak56 is required in presynapses to restrict NMJ growth. Genetic analyses imply that FAK mediates the signaling pathway of the integrin αPS3βν heterodimer and functions redundantly with Src. At NMJs, Fak56 downregulates ERK activity, as shown by diphospho-ERK accumulation in Fak56 mutants, and suppression of Fak56 mutant NMJ phenotypes by reducing ERK activity.We conclude that Fak56 is required to restrict NMJ growth during NMJ development. Fak56 mediates an extracellular signal through the integrin receptor. Unlike its conventional role in activating MAPK/ERK, Fak56 suppresses ERK activation in this process. These results suggest that Fak56 mediates a specific neuronal signaling pathway distinct from that in other cellular processes.Formation and stabilization of neuronal synapses demands communication between pre- and post-synaptic partners, as well as signals from the extracellular matrix (ECM). These signals can reorganize local cytoskeletal structures or be transduced into the nucleus to regulate transcription, thereby modulating neuronal plasticity [1-3]. One major receptor family for ECM signals comprises the transmembrane protein integrins, which have been shown to play critical roles in sequential steps of neuronal wiring, such as in neurite outgrowth, axon guidance, and synaptic formation and maturation [4-7]. In Drosophila, various integrin subunits have been shown to function in motor axon pathfinding and target recognition, and synaptic morphogenesis at neuromuscular junctions (NMJs) [8-10]. Mutant analyses for the integrin subunits αPS3 and βPS indicate that integrin signaling is involved in synaptic growth and arborization of larval NMJs [8-10]. Although specific ECM signals for these integrin receptors are not clear, dynamic NMJ growth is regulated
Human Capital and Inappropriate Behavior: Review and Recommendations  [PDF]
David D. Van Fleet
Journal of Human Resource and Sustainability Studies (JHRSS) , 2018, DOI: 10.4236/jhrss.2018.64042
Abstract: Human capital is vital to the successful operation of any organization, the quality of which is threatened by inappropriate organizational behavior. Reducing or eliminating such behavior is critical. Organizations must establish a positive atmosphere that guarantees the rights of all employees to a workplace free from all forms of inappropriate behavior. Morrison proposed eight “people-focused principles of management” that would enable managers to activate and fully utilize the human capital in their organizations. This preliminary study suggests that adopting those principles would benefit organizations.
The Classification of the Tineidae
Vactor Tousey Chambers
Psyche , 1883, DOI: 10.1155/1883/48181
Notes Upon Some Tineid Larvae
Vactor Tousey Chambers
Psyche , 1880, DOI: 10.1155/1880/38474
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