scholarly journals The activity-dependent transcription factor Npas4 regulates IQSEC3 expression in somatostatin interneurons to mediate anxiety-like behavior

2019 ◽  
Author(s):  
Seungjoon Kim ◽  
Dongseok Park ◽  
Jinhu Kim ◽  
Dongsoo Lee ◽  
Dongwook Kim ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Synaptic Transmission ◽  
Molecular Mechanisms ◽  
Dominant Negative ◽  
Normal Brain ◽  
Gabaergic Synapse ◽  
Iq Motif ◽  
Brain Functions ◽  
Activity Dependent ◽  
Gabaergic Synaptic Transmission

AbstractOrganization of mammalian inhibitory synapses is thought to be crucial for normal brain functions, but the underlying molecular mechanisms have been still incompletely understood. IQSEC3 (IQ motif and Sec7 domain 3) is a guanine nucleotide exchange factor for ADP-ribosylation factor (ARF-GEF) that directly interacts with gephyrin. Here, we show that GABAergic synapse-specific transcription factor, Npas4 (neuronal PAS domain protein 4) directly binds to the promoter of Iqsec3 and regulates its transcription. Strikingly, an enriched environment (EE) induced Npas4 upregulation and concurrently increased IQSEC3 protein levels specifically in mouse CA1 stratum oriens layer somatostatin (SST)-expressing GABAergic interneurons, which are compromised in Npas4-knockout (KO) mice. Moreover, expression of wild-type (WT) IQSEC3, but not a dominant-negative (DN) ARF-GEF–inactive mutant, rescued the decreased GABAergic synaptic transmission in Npas4-deficient SST interneurons. Concurrently, expression of IQSEC3 WT normalized the altered GABAergic synaptic transmission in dendrites, but not soma, of Npas4-deficient CA1 pyramidal neurons. Furthermore, expression of IQSEC3 WT, but not IQSEC3 DN, in SST-expressing interneurons in CA1 SST Npas4-KO mice rescued the altered anxiety-like behavior. Collectively, our results suggest that IQSEC3 is a key GABAergic synapse component that is directed by Npas4 activity- and ARF activity-dependent gene programs in SST-expressing interneurons to orchestrate the functional excitation-to-inhibition balance.

scholarly journals A CCAAT/Enhancer Binding Protein β Isoform, Liver-Enriched Inhibitory Protein, Regulates Commitment of Osteoblasts and Adipocytes

2005 ◽  
Vol 25 (5) ◽  
pp. 1971-1979 ◽  
Author(s):  
Kenji Hata ◽  
Riko Nishimura ◽  
Mio Ueda ◽  
Fumiyo Ikeda ◽  
Takuma Matsubara ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Osteoblast Differentiation ◽  
Molecular Mechanisms ◽  
Binding Protein ◽  
Mesenchymal Cells ◽  
Dominant Negative ◽  
Inhibitory Protein ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein

ABSTRACT Although both osteoblasts and adipocytes have a common origin, i.e., mesenchymal cells, the molecular mechanisms that define the direction of two different lineages are presently unknown. In this study, we investigated the role of a transcription factor, CCAAT/enhancer binding protein β (C/EBPβ), and its isoform in the regulation of balance between osteoblast and adipocyte differentiation. We found that C/EBPβ, which is induced along with osteoblast differentiation, promotes the differentiation of mesenchymal cells into an osteoblast lineage in cooperation with Runx2, an essential transcription factor for osteogenesis. Surprisingly, an isoform of C/EBPβ, liver-enriched inhibitory protein (LIP), which lacks the transcriptional activation domain, stimulates transcriptional activity and the osteogenic action of Runx2, although LIP inhibits adipogenesis in a dominant-negative fashion. Furthermore, LIP physically associates with Runx2 and binds to the C/EBP binding element present in the osteocalcin gene promoter. These data indicate that LIP functions as a coactivator for Runx2 and preferentially promotes the osteoblast differentiation of mesenchymal cells. Thus, identification of a novel role of the C/EBPβ isoform provides insight into the molecular basis of the regulation of osteoblast and adipocyte commitment.

scholarly journals Astrocyte Networks and Epilepsy: When Stars Collide

2009 ◽  
Vol 9 (4) ◽  
pp. 113-115 ◽  
Author(s):  
Michael Wong
Keyword(s):  
Synaptic Transmission ◽  
Gap Junctions ◽  
Connexin 43 ◽  
Molecular Mechanisms ◽  
Epileptiform Activity ◽  
Synaptic Activity ◽  
Structural Basis ◽  
Dependent Manner ◽  
Domain Organization ◽  
Activity Dependent

Loss of Astrocytic Domain Organization in the Epileptic Brain. Oberheim NA, Tian GF, Han X, Peng W, Takano T, Ransom B, Nedergaard M. J Neurosci 2008;28(13):3264–3276. Gliosis is a pathological hallmark of posttraumatic epileptic foci, but little is known about these reactive astrocytes beyond their high glial fibrillary acidic protein (GFAP) expression. Using diolistic labeling, we show that cortical astrocytes lost their nonoverlapping domain organization in three mouse models of epilepsy: posttraumatic injury, genetic susceptibility, and systemic kainate exposure. Neighboring astrocytes in epileptic mice showed a 10-fold increase in overlap of processes. Concurrently, spine density was increased on dendrites of excitatory neurons. Suppression of seizures by the common antiepileptic, valproate, reduced the overlap of astrocytic processes. Astrocytic domain organization was also preserved in APP transgenic mice expressing a mutant variant of human amyloid precursor protein despite a marked upregulation of GFAP. Our data suggest that loss of astrocytic domains was not universally associated with gliosis, but restricted to seizure pathologies. Reorganization of astrocytes may, in concert with dendritic sprouting and new synapse formation, form the structural basis for recurrent excitation in the epileptic brain. Astroglial Metabolic Networks Sustain Hippocampal Synaptic Transmission. Rouach N, Koulakoff A, Abudara V, Willecke K, Giaume C. Science 2008;322(5907):1551–1555. Astrocytes provide metabolic substrates to neurons in an activity-dependent manner. However, the molecular mechanisms involved in this function, as well as its role in synaptic transmission, remain unclear. Here, we show that the gap-junction subunit proteins connexin 43 and 30 allow intercellular trafficking of glucose and its metabolites through astroglial networks. This trafficking is regulated by glutamatergic synaptic activity mediated by AMPA receptors. In the absence of extracellular glucose, the delivery of glucose or lactate to astrocytes sustains glutamatergic synaptic transmission and epileptiform activity only when they are connected by gap junctions. These results indicate that astroglial gap junctions provide an activity-dependent intercellular pathway for the delivery of energetic metabolites from blood vessels to distal neurons.

scholarly journals Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wei Yao ◽  
Song Lin ◽  
Jin Su ◽  
Qianqian Cao ◽  
Yueyue Chen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Synaptic Transmission ◽  
Molecular Mechanisms ◽  
Brain Regions ◽  
Related Factor ◽  
Transcriptional Repressors ◽  
Protein Levels ◽  
Repressor Proteins ◽  
Chronic Social Defeat Stress ◽  
Fast Acting

AbstractThe transcription factor erythroid 2-related factor 2 (Nrf2) and brain-derived neurotrophic factor (BDNF) play a key role in depression. However, the molecular mechanisms underlying the crosstalk between Nrf2 and BDNF in depression remain unclear. We examined whether Nrf2 regulates the transcription of Bdnf by binding to its exon I promoter. Furthermore, the role of Nrf2 and BDNF in the brain regions from mice with depression-like phenotypes was examined. Nrf2 regulated the transcription of Bdnf by binding to its exon I promoter. Activation of Nrf2 by sulforaphane (SFN) showed fast-acting antidepressant-like effects in mice by activating BDNF as well as by inhibiting the expression of its transcriptional repressors (HDAC2, mSin3A, and MeCP2) and revising abnormal synaptic transmission. In contrast, SFN did not affect the protein expression of BDNF and its transcriptional repressor proteins in the medial prefrontal cortex (mPFC) and hippocampus, nor did it reduce depression-like behaviors and abnormal synaptic transmission in Nrf2 knockout mice. In the mouse model of chronic social defeat stress (CSDS), protein levels of Nrf2 and BDNF in the mPFC and hippocampus were lower than those of control and CSDS-resilient mice. In contrast, the protein levels of BDNF transcriptional repressors in the CSDS-susceptible mice were higher than those of control and CSDS-resilient mice. These data suggest that Nrf2 activation increases the expression of Bdnf and decreases the expression of its transcriptional repressors, which result in fast-acting antidepressant-like actions. Furthermore, abnormalities in crosstalk between Nrf2 and BDNF may contribute to the resilience versus susceptibility of mice against CSDS.

scholarly journals Surveillance, Phagocytosis, and Inflammation: How Never-Resting Microglia Influence Adult Hippocampal Neurogenesis

2014 ◽  
Vol 2014 ◽  
pp. 1-15 ◽  
Author(s):  
Amanda Sierra ◽  
Sol Beccari ◽  
Irune Diaz-Aparicio ◽  
Juan M. Encinas ◽  
Samuel Comeau ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Cells ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Trophic Factors ◽  
Normal Brain ◽  
Positive Contribution ◽  
Brain Functions ◽  
Wide Range ◽  
Trauma Injury

Microglia cells are the major orchestrator of the brain inflammatory response. As such, they are traditionally studied in various contexts of trauma, injury, and disease, where they are well-known for regulating a wide range of physiological processes by their release of proinflammatory cytokines, reactive oxygen species, and trophic factors, among other crucial mediators. In the last few years, however, this classical view of microglia was challenged by a series of discoveries showing their active and positive contribution to normal brain functions. In light of these discoveries, surveillant microglia are now emerging as an important effector of cellular plasticity in the healthy brain, alongside astrocytes and other types of inflammatory cells. Here, we will review the roles of microglia in adult hippocampal neurogenesis and their regulation by inflammation during chronic stress, aging, and neurodegenerative diseases, with a particular emphasis on their underlying molecular mechanisms and their functional consequences for learning and memory.

scholarly journals Haploinsufficiency of NPM1 in AML Derived NPM1 Mutant (NPMc+) Expressing Cells Contributes to Aberrant C/EBPα Activity

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2188-2188
Author(s):  
Kathryn Czepiel ◽  
Kelly Nichol ◽  
Mason Tippy ◽  
Nirmalee Abayasekara ◽  
Jaclyn Lee ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Nuclear Export ◽  
Molecular Mechanisms ◽  
Dominant Negative ◽  
Full Length ◽  
Wild Type ◽  
Cellular Models ◽  
Gene Assay ◽  
Factor C

Abstract Nucleophosmin 1 (NPM-1) is a highly conserved, ubiquitously expressed nucleolar protein that functions as a molecular chaperone shuttling protein-binding partners between the nucleolus, nucleus and cytoplasm. NPM-1 and has been assigned more than a dozen functions in the cell, including ribosome biogenesis and centrosome duplication. The NPM-1 gene maps to chromosome 5q35, a region that is the target of deletions in both de novo and therapy-associated MDS in humans. Additionally, heterozygous mutations in the NPM-1 gene have been identified in 60% of cytogenetically normal adult AMLs. Mutant NPM-1, (NPMc+), commonly results in the generation of a novel nuclear export signal (NES) leading to cellular mislocalization of NPMc+ from the nucleolus and nucleus to the cytoplasm. The role of NPMc+ in contributing to AML however remains unresolved to date. Two hypotheses to explain the role of NPMc+ in leukemogenesis have been advanced. The first purports that aberrant cytoplasmic mislocalization of NPMc+ also mislocalizes a number of NPM1-cargo proteins into the cytoplasm including for example, the tumor suppressor Arf, leading to the activation of the c-MYC oncogene, thereby contributing to leukeomogenesis. A second hypothesis states that reduction in wild type levels of NPM-1 in the nucleolus as a result of both heterozygosity as well as mislocalization into the cytoplasm following association with NPMc+, contributes to tumorigenesis. To address these hypotheses we generated a series of IL-3-dependent cell lines from the bone marrow of NPM1+/+ and NPM+/-mice. In addition, we stably transduced an NPMc+ expression vector into the NPM+/- cells resulting in the NPM+/-c+ line, thereby providing cellular models for both NPM1 haploinsufficieny as well as mutant NPM-1 associated AML. We then sought to examine the role of the master myeloid transcription factor C/EBPα in contributing to NPM-1-associated AML. C/EBPα is a single exon, bzip transcription factor that generates four isoforms derived from separate in-frame AUGs resulting in the translation of a nucleolar p50, a full length p42, a p40 and a dominant negative p30 isoform. We found that in NPM+/-c+ and OCI-AML3 cells (derived from a CN-AML patient harboring the NPMc+ mutation), only the p40 isoform of C/EBPα migrated to the cytoplasm while the full length p42 isofom remained in the nucleus. The p40 isoform of C/EBPα lacks the first 14 N-terminal amino acids when compared to the full length p42 isoform, and its function has not been well described in the literature. However, we have demonstrated that like the full length p42 isoform, the p40 isoform is also capable of transcriptional activation as measured by a reporter gene assay. Hence mislocalization of p40 could affect the overall activity of C/EBPα in NPMc+ expressing cells. We next sought to determine the contribution of NPM-1 haploinsufficieny to C/EBPα activity using our NPM+/- cells. We showed that a) expression levels of the dominant negative p30 isoform of C/EBPα are elevated in NPM+/- cells thereby blocking the activity of wildtype p42 b) C/EBPα p42 protein in the nucleus is rendered inactive due to phosphorylation by an unknown kinase at the S21position and c) expression of the downstream targets of C/EBPα (lactoferrin, MMP8, MMP9, gp91phox) are blocked in NPM+/- cells. These observations together suggest that in CN-AML where one copy of NPM-1 is wildtype and one copy is mutant (NPMc+), both haploinsufficient levels of wild type NPM-1 as well as mutant NPMc+ contribute to aberrant myeloid differentiation by inactivating C/EBPα activity. Our data thus provide new insights into the molecular mechanisms of mutant NPM-1 associated AML. Disclosures No relevant conflicts of interest to declare.

scholarly journals Pendrin Is a Novel In Vivo Downstream Target Gene of the TTF-1/Nkx-2.1 Homeodomain Transcription Factor in Differentiated Thyroid Cells

2005 ◽  
Vol 25 (22) ◽  
pp. 10171-10182 ◽  
Author(s):  
Monica Dentice ◽  
Cristina Luongo ◽  
Antonia Elefante ◽  
Raffaele Ambrosio ◽  
Salvatore Salzano ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Homeobox Gene ◽  
Dominant Negative ◽  
Specific Gene ◽  
Thyroid Cells ◽  
Downstream Target ◽  
C Terminus ◽  
Downstream Target Gene

ABSTRACT Thyroid transcription factor gene 1 (TTF-1) is a homeobox-containing gene involved in thyroid organogenesis. During early thyroid development, the homeobox gene Nkx-2.5 is expressed in thyroid precursor cells coincident with the appearance of TTF-1. The aim of this study was to investigate the molecular mechanisms underlying thyroid-specific gene expression. We show that the Nkx-2.5 C terminus interacts with the TTF-1 homeodomain and, moreover, that the expression of a dominant-negative Nkx-2.5 isoform (N188K) in thyroid cells reduces TTF-1-driven transcription by titrating TTF-1 away from its target DNA. This process reduced the expression of several thyroid-specific genes, including pendrin and thyroglobulin. Similarly, down-regulation of TTF-1 by RNA interference reduced the expression of both genes, whose promoters are sensitive to and directly associate with TTF-1 in the chromatin context. In conclusion, we demonstrate that pendrin and thyroglobulin are downstream targets in vivo of TTF-1, whose action is a prime factor in controlling thyroid differentiation in vivo.

scholarly journals Molecular Mechanisms Underlying Activity-Dependent GABAergic Synapse Development and Plasticity and Its Implications for Neurodevelopmental Disorders

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Bidisha Chattopadhyaya
Keyword(s):  
Neurodevelopmental Disorders ◽  
Critical Period ◽  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Neural Circuits ◽  
Normal Function ◽  
Gabaergic Synapse ◽  
Synapse Maturation ◽  
Circuit Development ◽  
Activity Dependent

GABAergic interneurons are critical for the normal function and development of neural circuits, and their dysfunction is implicated in a large number of neurodevelopmental disorders. Experience and activity-dependent mechanisms play an important role in GABAergic circuit development, also recent studies involve a number of molecular players involved in the process. Emphasizing the molecular mechanisms of GABAergic synapse formation, in particular basket cell perisomatic synapses, this paper draws attention to the links between critical period plasticity, GABAergic synapse maturation, and the consequences of its dysfunction on the development of the nervous system.

scholarly journals Ca2+ influx–independent synaptic potentiation mediated by mitochondrial Na+-Ca2+ exchanger and protein kinase C

2003 ◽  
Vol 163 (3) ◽  
pp. 511-523 ◽  
Author(s):  
Feng Yang ◽  
Xiang-ping He ◽  
James Russell ◽  
Bai Lu
Keyword(s):  
Synaptic Transmission ◽  
Synaptic Potentiation ◽  
Tetanic Stimulation ◽  
Free Medium ◽  
Synaptic Modulation ◽  
Brain Functions ◽  
Neuromuscular Synapses ◽  
Kinase C ◽  
Activity Dependent

Activity-dependent modulation of synaptic transmission is an essential mechanism underlying many brain functions. Here we report an unusual form of synaptic modulation that depends on Na+ influx and mitochondrial Na+-Ca2+ exchanger, but not on Ca2+ influx. In Ca2+-free medium, tetanic stimulation of Xenopus motoneurons induced a striking potentiation of transmitter release at neuromuscular synapses. Inhibition of either Na+ influx or the rise of Ca2+ concentrations ([Ca2+]i) at nerve terminals prevented the tetanus-induced synaptic potentiation (TISP). Blockade of Ca2+ release from mitochondrial Na+-Ca2+ exchanger, but not from ER Ca2+ stores, also inhibited TISP. Tetanic stimulation in Ca2+-free medium elicited an increase in [Ca2+]i, which was prevented by inhibition of Na+ influx or mitochondrial Ca2+ release. Inhibition of PKC blocked the TISP as well as mitochondrial Ca2+ release. These results reveal a novel form of synaptic plasticity and suggest a role of PKC in mitochondrial Ca2+ release during synaptic transmission.

Transcription factor/DNA interactions visualized by electron spectroscopic imaging

1992 ◽  
Vol 50 (1) ◽  
pp. 450-451
Author(s):  
David P. Bazett-Jones ◽  
Mark L. Brown
Keyword(s):  
Transcription Factor ◽  
Dna Sequences ◽  
Transcription Initiation ◽  
Molecular Mechanisms ◽  
Phosphorus Content ◽  
Spectroscopic Imaging ◽  
Electron Spectroscopic Imaging ◽  
Dna Backbone ◽  
Two Parameters ◽  
High Level

A multisubunit RNA polymerase enzyme is ultimately responsible for transcription initiation and elongation of RNA, but recognition of the proper start site by the enzyme is regulated by general, temporal and gene-specific trans-factors interacting at promoter and enhancer DNA sequences. To understand the molecular mechanisms which precisely regulate the transcription initiation event, it is crucial to elucidate the structure of the transcription factor/DNA complexes involved. Electron spectroscopic imaging (ESI) provides the opportunity to visualize individual DNA molecules. Enhancement of DNA contrast with ESI is accomplished by imaging with electrons that have interacted with inner shell electrons of phosphorus in the DNA backbone. Phosphorus detection at this intermediately high level of resolution (≈lnm) permits selective imaging of the DNA, to determine whether the protein factors compact, bend or wrap the DNA. Simultaneously, mass analysis and phosphorus content can be measured quantitatively, using adjacent DNA or tobacco mosaic virus (TMV) as mass and phosphorus standards. These two parameters provide stoichiometric information relating the ratios of protein:DNA content.

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