scholarly journals The schizophrenia- and autism-associated gene, transcription factor 4 regulates the columnar distribution of layer 2/3 prefrontal pyramidal neurons in an activity-dependent manner

2017 ◽  
Vol 23 (2) ◽  
pp. 304-315 ◽  
Author(s):  
S C Page ◽  
G R Hamersky ◽  
R A Gallo ◽  
M D Rannals ◽  
N E Calcaterra ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Gene Transcription ◽  
Pyramidal Neurons ◽  
Dependent Manner ◽  
Layer 2 ◽  
Transcription Factor 4 ◽  
Activity Dependent

scholarly journals Parathyroid Hormone Increases Activating Transcription Factor 4 Expression and Activity in Osteoblasts: Requirement for Osteocalcin Gene Expression

Endocrinology ◽  
2008 ◽  
Vol 149 (4) ◽  
pp. 1960-1968 ◽  
Author(s):  
Shibing Yu ◽  
Renny T. Franceschi ◽  
Min Luo ◽  
Xiaoyan Zhang ◽  
Di Jiang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Kinase ◽  
Transcriptional Activity ◽  
De Novo ◽  
Dependent Manner ◽  
Specific Element ◽  
Activating Transcription Factor 4 ◽  
Activating Transcription Factor ◽  
Transcription Factor 4 ◽  
Expression And Activity

PTH is an important peptide hormone regulator of calcium homeostasis and osteoblast function. However, its mechanism of action in osteoblasts is poorly understood. Our previous study demonstrated that PTH activates mouse osteocalcin (Ocn) gene 2 promoter through the osteoblast-specific element 1 site, a recently identified activating transcription factor-4 (ATF4) -binding element. In the present study, we examined effects of PTH on ATF4 expression and activity as well as the requirement for ATF4 in the regulation of Ocn by PTH. Results show that PTH elevated levels of ATF4 mRNA and protein in a dose- and time-dependent manner. This PTH regulation requires transcriptional activity but not de novo protein synthesis. PTH also increased binding of nuclear extracts to osteoblast-specific element 1 DNA. PTH stimulated ATF4-dependent transcriptional activity mainly through protein kinase A with a lesser requirement for protein kinase C and MAPK/ERK pathways. Lastly, PTH stimulation of Ocn expression was lost by small interfering RNA down-regulation of ATF4 in MC-4 cells and Atf4−/− bone marrow stromal cells. Collectively, these studies for the first time demonstrate that PTH increases ATF4 expression and activity and that ATF4 is required for PTH induction of Ocn expression in osteoblasts.

scholarly journals Building a schizophrenia genetic network: Transcription Factor 4 regulates genes involved in neuronal development and schizophrenia risk

2017 ◽  
Author(s):  
Hanzhang Xia ◽  
Fay M. Jahr ◽  
Nak-Kyeong Kim ◽  
Linying Xie ◽  
Andrey A. Shabalin ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Binding Sites ◽  
Neuronal Development ◽  
Pyramidal Neurons ◽  
Genetic Network ◽  
Binding Motif ◽  
Gene Set ◽  
Chromatin Immunoprecipitation Sequencing ◽  
Sirna Knockdown ◽  
Transcription Factor 4

ABSTRACTThe transcription factor 4 (TCF4) locus is a robust association finding with schizophrenia (SZ), but little is known about the genes regulated by the encoded transcription factor. Therefore, we conducted chromatin immunoprecipitation sequencing (ChIP-seq) of TCF4 in neural-derived (SH-SY5Y) cells to identify genome-wide TCF4 binding sites, followed by data integration with SZ association findings. We identified 11,322 TCF4 binding sites overlapping in two ChIP-seq experiments. These sites are significantly enriched for the TCF4 Ebox binding motif (>85% having ≥1 Ebox) and implicate a gene set enriched for genes down-regulated in TCF4 siRNA knockdown experiments, indicating the validity of our findings. The TCF4 gene set was also enriched among 1) Gene Ontology categories such as axon/neuronal development, 2) genes preferentially expressed in brain, in particular pyramidal neurons of the somatosensory cortex, and 3) genes down-regulated in post-mortem brain tissue from SZ patients (OR=2.8, permutation p<4x10−5). Considering genomic alignments, TCF4 binding sites significantly overlapped those for neural DNA binding proteins such as FOXP2 and the SZ-associated EP300. TCF4 binding sites were modestly enriched among SZ risk loci from the Psychiatric Genomic Consortium (OR=1.56, p=0.03). In total, 130 TCF4 binding sites occurred in 39 of the 108 regions published in 2014. Thirteen genes within the 108 loci had both a TCF4 binding site ±10kb and were differentially expressed in siRNA knockdown experiments of TCF4, suggesting direct TCF4 regulation. These findings confirm TCF4 as an important regulator of neural genes and point towards functional interactions with potential relevance for SZ.

Early NMDA Receptor Ablation in Interneurons Causes an Activity-Dependent E/I Imbalance in vivo in Prefrontal Cortex Pyramidal Neurons of a Mouse Model Useful for the Study of Schizophrenia

2021 ◽  
Author(s):  
Diego E Pafundo ◽  
Carlos A Pretell Annan ◽  
Nicolas M Fulginiti ◽  
Juan E Belforte
Keyword(s):  
Prefrontal Cortex ◽  
Mouse Model ◽  
Pyramidal Neurons ◽  
Gamma Oscillations ◽  
Dependent Manner ◽  
Early Postnatal Development ◽  
Synaptic Inputs ◽  
Selective Ablation ◽  
Activity Dependent

Abstract Altered Excitatory/Inhibitory (E/I) balance of cortical synaptic inputs has been proposed as a central pathophysiological factor for psychiatric neurodevelopmental disorders, including schizophrenia (SZ). However, direct measurement of E/I synaptic balance have not been assessed in vivo for any validated SZ animal model. Using a mouse model useful for the study of SZ we show that a selective ablation of NMDA receptors (NMDAr) in cortical and hippocampal interneurons during early postnatal development results in an E/I imbalance in vivo, with synaptic inputs to pyramidal neurons shifted towards excitation in the adult mutant medial prefrontal cortex (mPFC). Remarkably, this imbalance depends on the cortical state, only emerging when theta and gamma oscillations are predominant in the network. Additional brain slice recordings and subsequent 3D morphological reconstruction showed that E/I imbalance emerges after adolescence concomitantly with significant dendritic retraction and dendritic spine re-localization in pyramidal neurons. Therefore, early postnatal ablation of NMDAr in cortical and hippocampal interneurons developmentally impacts on E/I imbalance in vivo in an activity-dependent manner.

scholarly journals Medial prefrontal cortical NMDA receptors regulate depression-like behavior and dictate limbic thalamus innervation

2017 ◽  
Author(s):  
Oliver H. Miller ◽  
Andreas Bruns ◽  
Imen Ben Ammar ◽  
Thomas Mueggler ◽  
Benjamin J. Hall
Keyword(s):  
Viral Vectors ◽  
Pyramidal Neurons ◽  
Synaptic Activity ◽  
Dependent Manner ◽  
Prefrontal Cortical ◽  
Limbic Thalamus ◽  
Level Function ◽  
Nmdar Subunit ◽  
Circuit Function ◽  
Activity Dependent

AbstractDepression is a pervasive and debilitating neuropsychiatric disorder. A single, low dose of the NMDA receptor (NMDAR) antagonist ketamine elicits a long-lasting antidepressant response in patients with treatment-resistant major depressive disorder. Developing mechanistic understanding of how NMDAR antagonism alters synapse and circuit function is pivotal to developing translatable, circuit-based therapies for depression. Here using viral vectors, anatomical tracing, fMRI, and optogenetic-assisted circuit analysis, we assessed the role of the NMDAR subunit GluN2B in regulating cellular, synaptic, and circuit-level function and depression-related behavior. We demonstrate that post-developmental deletion of GluN2B from pyramidal neurons in medial prefrontal cortex enhances action potential output in a synaptic activity-dependent manner. GluN2B deletion dictates functional connectivity between mPFC and limbic thalamus but not ventral hippocampus and elicits antidepressant-like behavior. Our findings demonstrate that postsynaptic GluN2B exerts input-specific control of pyramidal neuron innervation, and identify a novel circuit for regulating depression-like behaviors in mice.

scholarly journals HIC1 controls cellular- and HIV-1- gene transcription via interactions with CTIP2 and HMGA1

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Valentin Le Douce ◽  
Faezeh Forouzanfar ◽  
Sebastian Eilebrecht ◽  
Benoit Van Driessche ◽  
Amina Ait-Ammar ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Gene Transcription ◽  
Transcriptional Regulators ◽  
Viral Reservoir ◽  
Dependent Manner ◽  
Viral Promoter ◽  
Acetylation Status ◽  
Cellular Genes ◽  
The Brain ◽  
Hiv 1

Abstract Among many cellular transcriptional regulators, Bcl11b/CTIP2 and HGMA1 have been described to control the establishment and the persistence of HIV-1 latency in microglial cells, the main viral reservoir in the brain. In this present work, we identify and characterize a transcription factor i.e. HIC1, which physically interacts with both Bcl11b/CTIP2 and HMGA1 to co-regulate specific subsets of cellular genes and the viral HIV-1 gene. Our results suggest that HIC1 represses Tat dependent HIV-1 transcription. Interestingly, this repression of Tat function is linked to HIC1 K314 acetylation status and to SIRT1 deacetylase activity. Finally, we show that HIC1 interacts and cooperates with HGMA1 to regulate Tat dependent HIV-1 transcription. Our results also suggest that HIC1 repression of Tat function happens in a TAR dependent manner and that this TAR element may serve as HIC1 reservoir at the viral promoter to facilitate HIC1/TAT interaction.

scholarly journals Local autocrine signaling of IGF1 synthesized and released by CA1 pyramidal neurons regulates plasticity of dendritic spines

2021 ◽  
Author(s):  
Xun Tu ◽  
Anant Jain ◽  
Helena Decker ◽  
Ryohei Yasuda
Keyword(s):  
Synaptic Plasticity ◽  
Dendritic Spines ◽  
Pyramidal Neurons ◽  
Receptor Activation ◽  
Brain Regions ◽  
Dependent Manner ◽  
Autocrine Signaling ◽  
Ca1 Pyramidal Neurons ◽  
Igf1 Receptor ◽  
Activity Dependent

Insulin-like growth factor 1 (IGF1) regulates hippocampal plasticity, learning, and memory. While circulating, liver-derived IGF1 is known to play an essential role in hippocampal function and plasticity, IGF1 is also synthesized in multiple brain regions, including the hippocampus. However, little is known about the role of hippocampus-derived IGF1 in synaptic plasticity, the type of cells that may provide relevant IGF1, and the spatiotemporal dynamics of IGF1 signaling. Here, using a new FRET sensor for IGF1 signaling, we show that IGF1 in the hippocampus is primarily synthesized in CA1 pyramidal neurons and released in an activity-dependent manner in mice. The local IGF1 release from dendritic spines triggers local autocrine IGF1 receptor activation on the same spine, regulating structural and electrophysiological plasticity of the activated spine. Thus, our study demonstrates a novel mechanism underlying synaptic plasticity by the synthesis and autocrine signaling of IGF1 specific to CA1 pyramidal neurons.

scholarly journals 14-3-3 shuttles Activity-dependent neuroprotective protein to the cytoplasm to promote appropriate neuronal morphogenesis, cortical connectivity and calcium signaling

2020 ◽  
Author(s):  
Sarah A. Bennison ◽  
Sara M. Blazejewski ◽  
Xiaonan Liu ◽  
Kazuhito Toyo-oka
Keyword(s):  
Calcium Signaling ◽  
Pyramidal Neurons ◽  
Autism Spectrum ◽  
Neuronal Morphology ◽  
Cortical Connectivity ◽  
Neuronal Morphogenesis ◽  
Layer 2 ◽  
Neurite Formation ◽  
Activity Dependent

AbstractNeurite formation is the earliest stage of neuronal morphogenesis, where primitive dendrites and the primitive axon emerge from a spherical neuron and begin to elongate. Defective neuritogenesis is a contributing pathogenic mechanism behind a variety of neurodevelopmental disorders. Activity-dependent neuroprotective protein (Adnp) is essential to embryonic and postnatal brain development, and mutations in ADNP are among the most frequent underlying autism spectrum disorder (ASD). We found that knockdown of Adnp in vitro and in vivo in mouse layer 2/3 pyramidal neurons leads to increased neurite initiation and defective neurite elongation, suggesting that Adnp has distinct roles in each. In vivo analysis revealed that deficits begin at P0 and are sustained throughout development, the most notable of which include increased neurite stabilization, disrupted angle of the apical dendrite, increased basal dendrite number, and increased axon length. Because small changes in neuronal morphology can have large-scale effects on neuronal function and connectivity, we performed ex vivo calcium imaging to assess spontaneous function of layer 2/3 pyramidal neurons deficient in Adnp. This revealed that Adnp deficient neurons had a greater spontaneous calcium influx and a higher proportion of cells firing action potentials. Next, we utilized GRAPHIC, a novel synaptic tracing technology, to assess interhemispheric cortical connectivity. We found increased interhemispheric excitatory connectivity between Adnp deficient layer 2/3 pyramidal neurons. Because Adnp is a multifunctional protein with both transcription factor and cytoskeletal activity, we performed localization analysis of Adnp as neurons underwent neurite formation to probe the mechanism of our morphological defects. We found that Adnp is shuttled from the nucleus to the cytoplasm upon differentiation and this shuttling can be blocked via application of a global 14-3-3 inhibitor, difopein. Furthermore, we found that Adnp binds nuclear-cytoplasmic shuttle 14-3-3ε. We conclude that Adnp is shuttled from the nucleus to the cytoplasm by 14-3-3ε, where it regulates neuronal morphology, maturation, cortical connectivity, and calcium signaling.

scholarly journals The Psychiatric Risk Gene Transcription Factor 4 (TCF4) Regulates Neurodevelopmental Pathways Associated With Schizophrenia, Autism, and Intellectual Disability

2017 ◽  
Vol 44 (5) ◽  
pp. 1100-1110 ◽  
Author(s):  
Marc P Forrest ◽  
Matthew J Hill ◽  
David H Kavanagh ◽  
Katherine E Tansey ◽  
Adrian J Waite ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Intellectual Disability ◽  
Gene Transcription ◽  
Risk Gene ◽  
Transcription Factor 4
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