Cell type-specific effects ofYersinia pseudotuberculosisvirulence effectors

ABSTRACTBackgroundWhile their behavioral effects are well-characterized, the mechanisms by which anaesthetics induce loss of consciousness are largely unknown. Anaesthetics may disrupt integration and propagation of information in corticothalamic networks. Recent studies have shown that isoflurane diminishes synaptic responses of thalamocortical (TC) and corticocortical (CC) afferents in a pathway-specific manner. However, whether the synaptic effects of isoflurane observed in extracellular recordings persist at the cellular level has yet to be explored.MethodsHere, we activate TC and CC layer 1 inputs in non-primary mouse neocortex in ex vivo brain slices and explore the degree to which isoflurane modulates synaptic responses in pyramidal cells and in two inhibitory cell populations, somatostatin-positive (SOM+) and parvalbumin-positive (PV+) interneurons.ResultsWe show that the effects of isoflurane on synaptic responses and intrinsic properties of these cells varies among cell type and by cortical layer. Layer 1 inputs to L4 pyramidal cells were suppressed by isoflurane at both TC and CC synapses, while those to L2/3 pyramidal cells and PV+ interneurons were not. TC inputs to SOM+ cells were rarely observed at all, while CC inputs to SOM+ interneurons were robustly suppressed by isoflurane.ConclusionsThese results suggest a mechanism by which isoflurane disrupts integration and propagation of thalamocortical and intracortical signals.

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Cell type-specific effects of BDNF in modulating dendritic architecture of hippocampal neurons

Brain Structure and Function ◽

10.1007/s00429-018-1715-0 ◽

2018 ◽

Vol 223 (8) ◽

pp. 3689-3709 ◽

Cited By ~ 8

Author(s):

Marta Zagrebelsky ◽

N. Gödecke ◽

A. Remus ◽

Martin Korte

Keyword(s):

Hippocampal Neurons ◽

Cell Type ◽

Specific Effects ◽

Cell Type Specific

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Cell type-specific effects of p27KIP1 loss on retinal development

Neural Development ◽

10.1186/s13064-017-0094-1 ◽

2017 ◽

Vol 12 (1) ◽

Cited By ~ 4

Author(s):

Mariko Ogawa ◽

Fuminori Saitoh ◽

Norihiro Sudou ◽

Fumi Sato ◽

Hiroki Fujieda

Keyword(s):

Retinal Development ◽

Cell Type ◽

Specific Effects ◽

Cell Type Specific

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Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1719014115 ◽

2018 ◽

Vol 115 (5) ◽

pp. 1111-1116 ◽

Cited By ~ 21

Author(s):

Mitra Heshmati ◽

Hossein Aleyasin ◽

Caroline Menard ◽

Daniel J. Christoffel ◽

Meghan E. Flanigan ◽

...

Keyword(s):

Nucleus Accumbens ◽

Cell Type ◽

Dopamine D2 ◽

Disease States ◽

Specific Effects ◽

Chronic Social Defeat Stress ◽

Cell Type Specific ◽

Stress Susceptibility ◽

Cell Adhesion Proteins

Behavioral coping strategies are critical for active resilience to stress and depression; here we describe a role for neuroligin-2 (NLGN-2) in the nucleus accumbens (NAc). Neuroligins (NLGN) are a family of neuronal postsynaptic cell adhesion proteins that are constituents of the excitatory and inhibitory synapse. Importantly, NLGN-3 and NLGN-4 mutations are strongly implicated as candidates underlying the development of neuropsychiatric disorders with social disturbances such as autism, but the role of NLGN-2 in neuropsychiatric disease states is unclear. Here we show a reduction in NLGN-2 gene expression in the NAc of patients with major depressive disorder. Chronic social defeat stress in mice also decreases NLGN-2 selectively in dopamine D1-positive cells, but not dopamine D2-positive cells, within the NAc of stress-susceptible mice. Functional NLGN-2 knockdown produces bidirectional, cell-type-specific effects: knockdown in dopamine D1-positive cells promotes subordination and stress susceptibility, whereas knockdown in dopamine D2-positive cells mediates active defensive behavior. These findings establish a behavioral role for NAc NLGN-2 in stress and depression; provide a basis for targeted, cell-type specific therapy; and highlight the role of active behavioral coping mechanisms in stress susceptibility.

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Independent glial subtypes delay development and extend healthy lifespan upon reduced insulin-PI3K signalling

BMC Biology ◽

10.1186/s12915-020-00854-9 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Nathaniel S. Woodling ◽

Arjunan Rajasingam ◽

Lucy J. Minkley ◽

Alberto Rizzo ◽

Linda Partridge

Keyword(s):

Glial Cell ◽

Cell Types ◽

Therapeutic Interventions ◽

Developmental Timing ◽

Cell Type ◽

Specific Effects ◽

Trade Offs ◽

Distinct Cell ◽

Pi3k Signalling ◽

Cell Type Specific

Abstract Background The increasing age of global populations highlights the urgent need to understand the biological underpinnings of ageing. To this end, inhibition of the insulin/insulin-like signalling (IIS) pathway can extend healthy lifespan in diverse animal species, but with trade-offs including delayed development. It is possible that distinct cell types underlie effects on development and ageing; cell-type-specific strategies could therefore potentially avoid negative trade-offs when targeting diseases of ageing, including prevalent neurodegenerative diseases. The highly conserved diversity of neuronal and non-neuronal (glial) cell types in the Drosophila nervous system makes it an attractive system to address this possibility. We have thus investigated whether IIS in distinct glial cell populations differentially modulates development and lifespan in Drosophila. Results We report here that glia-specific IIS inhibition, using several genetic means, delays development while extending healthy lifespan. The effects on lifespan can be recapitulated by adult-onset IIS inhibition, whereas developmental IIS inhibition is dispensable for modulation of lifespan. Notably, the effects we observe on both lifespan and development act through the PI3K branch of the IIS pathway and are dependent on the transcription factor FOXO. Finally, IIS inhibition in several glial subtypes can delay development without extending lifespan, whereas the same manipulations in astrocyte-like glia alone are sufficient to extend lifespan without altering developmental timing. Conclusions These findings reveal a role for distinct glial subpopulations in the organism-wide modulation of development and lifespan, with IIS in astrocyte-like glia contributing to lifespan modulation but not to developmental timing. Our results enable a more complete picture of the cell-type-specific effects of the IIS network, a pathway whose evolutionary conservation in humans make it tractable for therapeutic interventions. Our findings therefore underscore the necessity for cell-type-specific strategies to optimise interventions for the diseases of ageing.

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Cell-Type Specific Effects of Endocytosis Inhibitors on 5-Hydroxytryptamine2A Receptor Desensitization and Resensitization Reveal an Arrestin-, GRK2-, and GRK5-Independent Mode of Regulation in Human Embryonic Kidney 293 Cells

Molecular Pharmacology ◽

10.1124/mol.60.5.1020 ◽

2001 ◽

Vol 60 (5) ◽

pp. 1020-1030 ◽

Cited By ~ 63

Author(s):

John A. Gray ◽

Douglas J. Sheffler ◽

Anushree Bhatnagar ◽

Jason A. Woods ◽

Sandra J. Hufeisen ◽

...

Keyword(s):

Receptor Desensitization ◽

Cell Type ◽

Human Embryonic Kidney ◽

Specific Effects ◽

293 Cells ◽

Cell Type Specific ◽

Independent Mode ◽

Mode Of Regulation

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Notch Signaling In B-ALL Reveals PLK1 As A Potential Therapeutic Target In B-ALL: PLK1-Selective Inhibitor Poloxin Modulates Cyclin B and P53 Pathways, Leading To Growth Arrest and Apoptosis

Blood ◽

10.1182/blood.v122.21.2912.2912 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2912-2912 ◽

Cited By ~ 1

Author(s):

Sankaranarayanan Kannan ◽

Mandy A Hall ◽

Leonard S Golfman ◽

Patrick A Zweidler-McKay

Keyword(s):

Cell Cycle ◽

Notch Signaling ◽

Growth Arrest ◽

Selective Inhibitor ◽

Cyclin B ◽

Cell Type ◽

Specific Effects ◽

Cell Cycle Regulator ◽

Cell Type Specific ◽

Novel Therapeutic

Abstract Background Notch is a well-known oncogene in T-ALL, yet appears to have tumor suppressor effects in B-ALL. These cell type-specific effects of Notch signaling mirror consequences seen in early lymphocyte development and raises the question of how Notch leads to such divergent consequences in closely related cell types. In exploring these Notch mechanisms we discovered a B-ALL specific Notch-mediated reduction in the cell cycle regulator Polo-like kinase-1 (PLK1), revealing a novel targetable kinase in B-ALL. Approach To explore the consequences of Notch-mediated down regulation of cell cycle regulator kinase PLK1, we targeted PLK1 kinase function with the novel PLK1-selective inhibitor poloxin in human B-ALL lines. Results PLK1 is highly expressed in B-ALL verses normal tissues (panel A), correlates with cyclin B expression, is expressed >2-fold higher in B-ALL with t(1;19) than other B-ALL samples, and may predict response of ALL to methotrexate. In our panel of human B-ALL cell lines poloxin induced G2/M growth arrest and decreased cell number by >80% (panel B), and decreased survival in B-ALL cells (>75% AnnexinV+, panel C). PLK1 inhibition led to tumor suppressor p53 stabilization, revealing >5-fold increase in p53 protein levels following poloxin treatment in B-ALL (panel D). Mechanistically, PLK1 inhibition leads to both cytoplasmic re-localization of cyclin B, disrupting the CDC2-cyclinB complex, as well as phosphorylation of p53 at Ser20, which destabilizes p53-MDM2 interaction and thus accumulation of p53. Conclusions While exploring the mechanisms of cell type-specific effects of Notch signaling in ALL, we have found a novel therapeutic target, the cell cycle regulator PLK1. Our findings reveal a novel therapeutic approach whereby PLK1-selective inhibition via poloxin induces growth arrest and apoptosis in human B-ALL via consequences on cyclin B and p53 pathways. Disclosures: No relevant conflicts of interest to declare.

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