scholarly journals The Snail transcription factor CES-1 regulates glutamatergic behavior in C. elegans

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0245587
Author(s):  
Lidia Park ◽  
Eric S. Luth ◽  
Kelsey Jones ◽  
Julia Hofer ◽  
Irene Nguyen ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Synaptic Plasticity ◽  
Ampa Receptor ◽  
Active Form ◽  
Cell Lineage ◽  
Receptor Expression ◽  
Loss Of Function ◽  
Major Mechanism

Regulation of AMPA-type glutamate receptor (AMPAR) expression and function alters synaptic strength and is a major mechanism underlying synaptic plasticity. Although transcription is required for some forms of synaptic plasticity, the transcription factors that regulate AMPA receptor expression and signaling are incompletely understood. Here, we identify the Snail family transcription factor ces-1 in an RNAi screen for conserved transcription factors that regulate glutamatergic behavior in C. elegans. ces-1 was originally discovered as a selective cell death regulator of neuro-secretory motor neuron (NSM) and I2 interneuron sister cells in C. elegans, and has almost exclusively been studied in the NSM cell lineage. We found that ces-1 loss-of-function mutants have defects in two glutamatergic behaviors dependent on the C. elegans AMPA receptor GLR-1, the mechanosensory nose-touch response and spontaneous locomotion reversals. In contrast, ces-1 gain-of-function mutants exhibit increased spontaneous reversals, and these are dependent on glr-1 consistent with these genes acting in the same pathway. ces-1 mutants have wild type cholinergic neuromuscular junction function, suggesting that they do not have a general defect in synaptic transmission or muscle function. The effect of ces-1 mutation on glutamatergic behaviors is not due to ectopic cell death of ASH sensory neurons or GLR-1-expressing neurons that mediate one or both of these behaviors, nor due to an indirect effect on NSM sister cell deaths. Rescue experiments suggest that ces-1 may act, in part, in GLR-1-expressing neurons to regulate glutamatergic behaviors. Interestingly, ces-1 mutants suppress the increased reversal frequencies stimulated by a constitutively-active form of GLR-1. However, expression of glr-1 mRNA or GFP-tagged GLR-1 was not decreased in ces-1 mutants suggesting that ces-1 likely promotes GLR-1 function. This study identifies a novel role for ces-1 in regulating glutamatergic behavior that appears to be independent of its canonical role in regulating cell death in the NSM cell lineage.

scholarly journals Rescue of a developmental arrest caused by a C. elegans heat-shock transcription-factor mutation by loss of ribosomal S6-kinase activity

2018 ◽  
Author(s):  
Peter Chisnell ◽  
T. Richard Parenteau ◽  
Elizabeth Tank ◽  
Kaveh Ashrafi ◽  
Cynthia Kenyon
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Heat Shock ◽  
Heat Shock Transcription Factor ◽  
Adult Longevity ◽  
Loss Of Function ◽  
S6 Kinase ◽  
Heat Shock Transcription Factors ◽  
C Elegans ◽  
Developmental Arrest

AbstractThe widely conserved heat-shock response, regulated by heat shock transcription factors, is not only essential for cellular stress resistance and adult longevity, but also for proper development. However, the genetic mechanisms by which heat-shock transcription factors regulate development are not well understood. In C. elegans, we conducted an unbiased genetic screen to identify mutations that could ameliorate the developmental arrest phenotype of a heat-shock factor mutant. Here we show that loss of the conserved translational activator rsks-1/S6-Kinase, a downstream effector of TOR kinase, can rescue the developmental-arrest phenotype of hsf-1 partial loss-of-function mutants. Unexpectedly, we show that the rescue is not likely caused by reduced translation, nor to activation of any of a variety of stress-protective genes and pathways. Our findings identify an as-yet unexplained regulatory relationship between the heat-shock transcription factor and the TOR pathway during C. elegans’ development.

scholarly journals Requirement of a Myocardin-Related Transcription Factor for Development of Mammary Myoepithelial Cells

2006 ◽  
Vol 26 (15) ◽  
pp. 5797-5808 ◽  
Author(s):  
Shijie Li ◽  
Shurong Chang ◽  
Xiaoxia Qi ◽  
James A. Richardson ◽  
Eric N. Olson
Keyword(s):  
Transcription Factor ◽  
Smooth Muscle ◽  
Myoepithelial Cell ◽  
Serum Response Factor ◽  
Cell Lineage ◽  
Myoepithelial Cells ◽  
Embryonic Cell ◽  
Loss Of Function ◽  
Muscle Gene Expression ◽  
Related Transcription Factor

ABSTRACT The mammary gland consists of a branched ductal system comprised of milk-producing epithelial cells that form ductile tubules surrounded by a myoepithelial cell layer that provides contractility required for milk ejection. Myoepithelial cells bear a striking resemblance to smooth muscle cells, but they are derived from a different embryonic cell lineage, and little is known of the mechanisms that control their differentiation. Members of the myocardin family of transcriptional coactivators cooperate with serum response factor to activate smooth muscle gene expression. We show that female mice homozygous for a loss-of-function mutation of the myocardin-related transcription factor A (MRTF-A) gene are unable to effectively nurse their offspring due to a failure in maintenance of the differentiated state of mammary myoepithelial cells during lactation, resulting in apoptosis of this cell population, a consequent inability to release milk, and premature involution. The phenotype of MRTF-A mutant mice reveals a specific and essential role for MRTF-A in mammary myoepithelial cell differentiation and points to commonalities in the transcriptional mechanisms that control differentiation of smooth muscle and myoepithelial cells.

scholarly journals Nr4a2 Transcription Factor in Hippocampal Synaptic Plasticity, Memory and Cognitive Dysfunction: A Perspective Review

2021 ◽  
Vol 14 ◽  
Author(s):  
Judit Català-Solsona ◽  
Alfredo J. Miñano-Molina ◽  
José Rodríguez-Álvarez
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Synaptic Plasticity ◽  
Nuclear Receptor ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Memory Formation ◽  
Synaptic Dysfunction ◽  
Hippocampal Synaptic Plasticity

Long-lasting changes of synaptic efficacy are largely mediated by activity-induced gene transcription and are essential for neuronal plasticity and memory. In this scenario, transcription factors have emerged as pivotal players underlying synaptic plasticity and the modification of neural networks required for memory formation and consolidation. Hippocampal synaptic dysfunction is widely accepted to underlie the cognitive decline observed in some neurodegenerative disorders including Alzheimer’s disease. Therefore, understanding the molecular pathways regulating gene expression profiles may help to identify new synaptic therapeutic targets. The nuclear receptor 4A subfamily (Nr4a) of transcription factors has been involved in a variety of physiological processes within the hippocampus, ranging from inflammation to neuroprotection. Recent studies have also pointed out a role for the activity-dependent nuclear receptor subfamily 4, group A, member 2 (Nr4a2/Nurr1) in hippocampal synaptic plasticity and cognitive functions, although the underlying molecular mechanisms are still poorly understood. In this review, we highlight the specific effects of Nr4a2 in hippocampal synaptic plasticity and memory formation and we discuss whether the dysregulation of this transcription factor could contribute to hippocampal synaptic dysfunction, altogether suggesting the possibility that Nr4a2 may emerge as a novel synaptic therapeutic target in brain pathologies associated to cognitive dysfunctions.

scholarly journals Reduction of the neuroprotective transcription factor Npas4 results in increased neuronal necrosis, inflammation and brain lesion size following ischaemia

2015 ◽  
Vol 36 (8) ◽  
pp. 1449-1463 ◽  
Author(s):  
Fong Chan Choy ◽  
Thomas S Klarić ◽  
Wai Khay Leong ◽  
Simon A Koblar ◽  
Martin D Lewis
Keyword(s):  
Cell Death ◽  
Transcription Factor ◽  
Cortical Neurons ◽  
Neuroprotective Effect ◽  
Critical Role ◽  
Brain Lesion ◽  
Lesion Size ◽  
Loss Of Function ◽  
Neuronal Necrosis ◽  
Ischaemic Brain

Stroke is the second leading cause of death and the most frequent cause of adult disability. Neuronal Per-Arnt-Sim domain protein 4 (Npas4) is an activity-dependent transcription factor whose expression is induced in various brain insults, including cerebral ischaemia. Although previous studies have demonstrated that Npas4 plays a critical role in protecting neurons against neurodegenerative insults, the neuroprotective effect of Npas4 in response to ischaemic brain injury remains unknown. In this study, we used a loss-of-function approach to examine the neuroprotective potential of Npas4 in the context of ischaemic damage. Using oxygen and glucose deprivation, we demonstrated that the knockdown of Npas4 in mouse cortical neurons resulted in increased susceptibility to cell death. The protective effect of Npas4 was further investigated in vivo using a photochemically-induced stroke model in mice. We found a significantly larger lesion size and increased neurodegeneration in Npas4 knockout mice as compared to wild-type mice. Moreover, we also showed that ablation of Npas4 caused an increase in activated astrocytes and microglia, pro-inflammatory cytokines interleukin-6 and tumour necrosis factor alpha levels and a switch from apoptotic to necrotic cell death. Taken together, these data suggest that Npas4 plays a neuroprotective role in ischaemic stroke by limiting progressive neurodegeneration and neuroinflammation.

Ultimate Precision: Targeting Cancer but Not Normal Self-replication

2018 ◽  
pp. 950-963 ◽  
Author(s):  
Vamsidhar Velcheti ◽  
David Schrump ◽  
Yogen Saunthararajah
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Terminal Differentiation ◽  
Loss Of Function ◽  
Partial Loss ◽  
Common Pathway ◽  
Lineage Differentiation ◽  
Self Replication ◽  
Pharmacologic Inhibition

Self-replication is the engine that drives all biologic evolution, including neoplastic evolution. A key oncotherapy challenge is to target this, the heart of malignancy, while sparing the normal self-replication mandatory for health and life. Self-replication can be demystified: it is activation of replication, the most ancient of cell programs, uncoupled from activation of lineage-differentiation, metazoan programs more recent in origin. The uncoupling can be physiologic, as in normal tissue stem cells, or pathologic, as in cancer. Neoplastic evolution selects to disengage replication from forward-differentiation where intrinsic replication rates are the highest, in committed progenitors that have division times measured in hours versus weeks for tissue stem cells, via partial loss of function in master transcription factors that activate terminal-differentiation programs (e.g., GATA4) or in the coactivators they use for this purpose (e.g., ARID1A). These loss-of-function mutations bias master transcription factor circuits, which normally regulate corepressor versus coactivator recruitment, toward corepressors (e.g., DNMT1) that repress rather than activate terminal-differentiation genes. Pharmacologic inhibition of the corepressors rebalances to coactivator function, activating lineage-differentiation genes that dominantly antagonize MYC (the master transcription factor coordinator of replication) to terminate malignant self-replication. Physiologic self-replication continues, because the master transcription factors in tissue stem cells activate stem cell, not terminal-differentiation, programs. Druggable corepressor proteins are thus the barriers between self-replicating cancer cells and the terminal-differentiation fates intended by their master transcription factor content. This final common pathway to oncogenic self-replication, being separate and distinct from the normal, offers the favorable therapeutic indices needed for clinical progress.

scholarly journals Forkhead Transcription Factors Are Critical Effectors of Cell Death and Cell Cycle Arrest Downstream of PTEN

2000 ◽  
Vol 20 (23) ◽  
pp. 8969-8982 ◽  
Author(s):  
Noriaki Nakamura ◽  
Shivapriya Ramaswamy ◽  
Francisca Vazquez ◽  
Sabina Signoretti ◽  
Massimo Loda ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Transcription Factors ◽  
Cell Cycle Arrest ◽  
Transcriptional Activation ◽  
Active Form ◽  
Forkhead Transcription Factors ◽  
Cycle Arrest ◽  
In Cells ◽  
Constitutively Active

ABSTRACT PTEN acts as a tumor suppressor, at least in part, by antagonizing phosphoinositide 3-kinase (PI3K)/Akt signaling. Here we show that Forkhead transcription factors FKHRL1 and FKHR, substrates of the Akt kinase, are aberrantly localized to the cytoplasm and cannot activate transcription in PTEN-deficient cells. Restoration of PTEN function restores FKHR to the nucleus and restores transcriptional activation. Expression of a constitutively active form of FKHR that cannot be phosphorylated by Akt produces the same effect as reconstitution of PTEN on PTEN-deficient tumor cells. Specifically, activated FKHR induces apoptosis in cells that undergo PTEN-mediated cell death and induces G1 arrest in cells that undergo PTEN-mediated cell cycle arrest. Furthermore, both PTEN and constitutively active FKHR induce p27KIP1 protein but not p21. These data suggest that Forkhead transcription factors are critical effectors of PTEN-mediated tumor suppression.

scholarly journals The BTB transcription factors ZBTB11 and ZFP131 maintain pluripotency by pausing POL II at pro-differentiation genes

2020 ◽  
Author(s):  
Görkem Garipler ◽  
Congyi Lu ◽  
Alexis Morrissey ◽  
Lorena S. Lopez-Zepeda ◽  
Simon E. Vidal ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Stem Cell ◽  
Transcription Factors ◽  
Embryonic Stem ◽  
Loss Of Function ◽  
Pluripotent Cells ◽  
Pol Ii ◽  
Crispr Screen ◽  
Rapid Activation ◽  
Factor Release

AbstractIn pluripotent cells, a delicate activation-repression balance maintains pro-differentiation genes ready for rapid activation. The identity of transcription factors (TFs) that specifically repress pro-differentiation genes remains obscure. By targeting ~1,700 TFs with CRISPR loss-of-function screen, we found that ZBTB11 and ZFP131 are required for embryonic stem cell (ESC) pluripotency. ZBTB11 and ZFP131 maintain promoter-proximally paused Polymerase II at pro-differentiation genes in ESCs. ZBTB11 or ZFP131 loss leads to NELF pausing factor release, an increase in H3K4me3, and transcriptional upregulation of genes associated with all three germ layers. Together, our results suggest that ZBTB11 and ZFP131 maintain pluripotency by preventing premature expression of pro-differentiation genes and present a generalizable framework to maintain cellular potency.One-sentence summaryA Transcription Factor-wide CRISPR screen identifies ZBTB11 and ZFP131 maintaining pluripotency by pausing POL II at pro-differentiation genes

scholarly journals Single-molecule conformational dynamics of a transcription factor reveals a continuum of binding modes controlling association and dissociation

2021 ◽  
Author(s):  
Wei Chen ◽  
Wei Lu ◽  
Peter G Wolynes ◽  
Elizabeth A Komives
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Single Molecule ◽  
Bound States ◽  
Conformational Dynamics ◽  
Conformational Ensemble ◽  
Binding Modes ◽  
Loss Of Function ◽  
Binding Domains

Abstract Binding and unbinding of transcription factors to DNA are kinetically controlled to regulate the transcriptional outcome. Control of the release of the transcription factor NF-κB from DNA is achieved through accelerated dissociation by the inhibitor protein IκBα. Using single-molecule FRET, we observed a continuum of conformations of NF-κB in free and DNA-bound states interconverting on the subseconds to minutes timescale, comparable to in vivo binding on the seconds timescale, suggesting that structural dynamics directly control binding kinetics. Much of the DNA-bound NF-κB is partially bound, allowing IκBα invasion to facilitate DNA dissociation. IκBα induces a locked conformation where the DNA-binding domains of NF-κB are too far apart to bind DNA, whereas a loss-of-function IκBα mutant retains the NF-κB conformational ensemble. Overall, our results suggest a novel mechanism with a continuum of binding modes for controlling association and dissociation of transcription factors.

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