scholarly journals Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of the synaptic proteome

2020 ◽  
Vol 13 (7) ◽  
pp. dmm042747 ◽  
Author(s):  
Laura Tamberg ◽  
Mariliis Jaago ◽  
Kristi Säälik ◽  
Alex Sirp ◽  
Jürgen Tuvikene ◽  
...  
Keyword(s):  
Associative Learning ◽  
Target Genes ◽  
Fruit Fly ◽  
Synaptic Proteins ◽  
Gal4 Driver ◽  
Negative Geotaxis ◽  
Discs Large ◽  
Behavioural Phenotypes ◽  
Direct Target ◽  
Transcription Factor 4

ABSTRACTMammalian transcription factor 4 (TCF4) has been linked to schizophrenia and intellectual disabilities, such as Pitt–Hopkins syndrome (PTHS). Here, we show that similarly to mammalian TCF4, fruit fly orthologue Daughterless (Da) is expressed widely in the Drosophila brain. Furthermore, silencing of da, using several central nervous system-specific Gal4 driver lines, impairs appetitive associative learning of the larvae and leads to decreased levels of the synaptic proteins Synapsin (Syn) and Discs large 1 (Dlg1), suggesting the involvement of Da in memory formation. Here, we demonstrate that Syn and dlg1 are direct target genes of Da in adult Drosophila heads, as Da binds to the regulatory regions of these genes and the modulation of Da levels alter the levels of Syn and dlg1 mRNA. Silencing of da also affects negative geotaxis of the adult flies, suggesting the impairment of locomotor function. Overall, our findings suggest that Da regulates Drosophila larval memory and adult negative geotaxis, possibly via its synaptic target genes Syn and dlg1. These behavioural phenotypes can be further used as a PTHS model to screen for therapeutics.This article has an associated First Person interview with the first author of the paper.

scholarly journals Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of synaptic proteome

2019 ◽  
Author(s):  
Laura Tamberg ◽  
Mariliis Jaago ◽  
Kristi Säälik ◽  
Anastassia Shubina ◽  
Carl Sander Kiir ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Associative Learning ◽  
Target Genes ◽  
Brain Structures ◽  
Fruit Fly ◽  
Synaptic Proteins ◽  
Bhlh Transcription Factor ◽  
Negative Geotaxis ◽  
Summary Statement ◽  
Transcription Factor 4

AbstractMammalian Transcription Factor 4 (TCF4) has been linked to schizophrenia and intellectual disabilities like Pitt-Hopkins syndrome (PTHS). Here we show that similarly to mammalian TCF4, fruit fly orthologue Daughterless (Da) is expressed in the Drosophila brain structures associated with learning and memory, the mushroom bodies. Furthermore, silencing of da in mushroom body neurons impairs appetitive associative learning of the larvae and leads to decreased levels of the synaptic proteins Synapsin (Syn) and discs large 1 (dlg1) suggesting the involvement of Da in memory formation. Here we demonstrate that Syn and dlg1 are direct target genes of Da in adult Drosophila heads, since Da binds to the regulatory regions of these genes and the modulation of Da levels alter the levels of Syn and dlg1 mRNA. Silencing of da also affects negative geotaxis of the adult flies suggesting the impairment of locomotor function. Overall, our findings suggest that Da regulates Drosophila larval memory and adult negative geotaxis possibly via its synaptic target genes Syn and dlg1. These behavioural phenotypes can be further used as a PTHS model to screen for therapeutics.Summary statementHuman TCF4, a bHLH transcription factor, is associated with intellectual disability and schizophrenia. Here we propose a Drosophila model for human disease studies using TCF4 orthologue in fruit fly, Daughterless.

MiRNA-145 and Its Direct Downstream Targets in Digestive System Cancers: A Promising Therapeutic Target

2020 ◽  
Vol 26 ◽  
Author(s):  
Yini Ma ◽  
Xiu Cao ◽  
Guojuan Shi ◽  
Tianlu Shi
Keyword(s):  
Digestive System ◽  
Target Genes ◽  
Malignant Neoplasm ◽  
Vital Role ◽  
Diagnostic Biomarkers ◽  
Cellular Processes ◽  
Promising Therapeutic Target ◽  
Direct Target ◽  
Potential Strategy

: MicroRNAs (miRNAs) play a vital role in the onset and development of many diseases, including cancers. Emerging evidence shows that numerous miRNAs have the potential to be used as diagnostic biomarkers for cancers, and miRNA-based therapy may be a promising therapy for the treatment of malignant neoplasm. MicroRNA-145 (miR-145) has been considered to play certain roles in various cellular processes, such as proliferation, differentiation and apoptosis, via modulating expression of direct target genes. Recent reports show that miR-145 participates in the progression of digestive system cancers, and plays crucial and novel roles for cancer treatment. In this review, we summarize the recent knowledge concerning the function of miR-145 and its direct targets in digestive system cancers. We discuss the potential role of miR-145 as valuable biomarkers for digestive system cancers and how miR-145 regulates these digestive system cancers via different targets to explore the potential strategy of targeting miR-145.

scholarly journals Human Bone Marrow Mesenchymal Stromal Cell-Derived Extracellular Vesicles Promote Proliferation of Degenerated Nucleus Pulposus Cells and the Synthesis of Extracellular Matrix Through the SOX4/Wnt/β-Catenin Axis

2021 ◽  
Vol 12 ◽  
Author(s):  
Haoyu Wang ◽  
Fei Li ◽  
Wenrui Ban ◽  
Jing Zhang ◽  
Guiqi Zhang
Keyword(s):  
Extracellular Matrix ◽  
Nucleus Pulposus ◽  
Extracellular Vesicles ◽  
Target Genes ◽  
Intervertebral Disk ◽  
Human Bone ◽  
Nucleus Pulposus Cells ◽  
Synthetic Genes ◽  
Downstream Target ◽  
Transcription Factor 4

Objective: Intervertebral disk degeneration (IDD) is a major cause of pain in the back, neck, and radiculus. Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) are therapeutic in musculoskeletal degenerative diseases such as IDD. This study explored the effect and functional mechanism of human bone MSCs (hBMSCs)-derived EVs in proliferation and apoptosis of degenerated nucleus pulposus cells (DNPCs) and extracellular matrix (ECM) synthesis.Methods: Extracellular vesicles were isolated from hBMSCs and identified. DNPCs were induced by TNF-α. EVs were incubated with DNPCs for 24h. Internalization of EVs by DNPCs, DNPCs proliferation, apoptosis, and expressions of ECM synthetic genes, degrading genes and miR-129-5p were assessed. Downstream target genes of miR-129-5p were predicted. Target relation between miR-129-5p and SRY-box transcription factor 4 (SOX4) was verified. DNPCs proliferation, apoptosis, and ECM synthesis were measured after treatment with EVs and miR-129-5p inhibitor or SOX4 overexpression. Expressions of SOX4 and Wnt/β-catenin pathway-related proteins were determined.Results: hBMSC-EVs promoted DNPCs proliferation, inhibited apoptosis, increased expressions of ECM synthetic genes, and reduced expressions of ECM degrading genes. hBMSC-EVs carried miR-129-5p into DNPCs. Silencing miR-129-5p in EVs partially inverted the effect of EVs on DNPCs proliferation and ECM synthesis. miR-129-5p targeted SOX4. SOX4 overexpression annulled the effect of EVs on DNPCs proliferation and ECM synthesis. Expressions of Wnt1 and β-catenin were decreased in EVs-treated DNPCs, while silencing miR-129-5p in EVs promoted expressions of Wnt1 and β-catenin.Conclusion: hBMSC-EVs promoted DNPCs proliferation and ECM synthesis by carrying miR-129-5p into DNPCs to target SOX4 and deactivating the Wnt/β-catenin axis.

scholarly journals Central clock components modulate plant shade avoidance by directly repressing transcriptional activation activity of PIF proteins

2020 ◽  
Vol 117 (6) ◽  
pp. 3261-3269 ◽  
Author(s):  
Yu Zhang ◽  
Anne Pfeiffer ◽  
James M. Tepperman ◽  
Jutta Dalton-Roesler ◽  
Pablo Leivar ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Target Genes ◽  
Direct Action ◽  
Published Data ◽  
Shade Avoidance ◽  
Response Regulators ◽  
Genome Wide ◽  
Promoter Occupancy ◽  
Factor Abundance ◽  
Direct Target

Light-environment signals, sensed by plant phytochrome photoreceptors, are transduced to target genes through direct regulation of PHYTOCHROME-INTERACTING FACTOR (PIF) transcription factor abundance and activity. Previous genome-wide DNA-binding and expression analysis has identified a set of genes that are direct targets of PIF transcriptional regulation. However, quantitative analysis of promoter occupancy versus expression level has suggested that unknown “trans factors” modulate the intrinsic transcriptional activation activity of DNA-bound PIF proteins. Here, using computational analysis of published data, we have identified PSEUDO-RESPONSE REGULATORS (PRR5 and PRR7) as displaying a high frequency of colocalization with the PIF proteins at their binding sites in the promoters of PIF Direct Target Genes (DTGs). We show that the PRRs function to suppress PIF-stimulated growth in the light and vegetative shade and that they repress the rapid PIF-induced expression of PIF-DTGs triggered by exposure to shade. The repressive action of the PRRs on both growth and DTG expression requires the PIFs, indicating direct action on PIF activity, rather than a parallel antagonistic pathway. Protein interaction assays indicate that the PRRs exert their repressive activity by binding directly to the PIF proteins in the nucleus. These findings support the conclusion that the PRRs function as direct outputs from the core circadian oscillator to regulate the expression of PIF-DTGs through modulation of PIF transcriptional activation activity, thus expanding the roles of the multifunctional PIF-signaling hub.

Effect of fruit and host fly species on the associative learning by Fopius arisanus

2019 ◽  
Vol 109 (05) ◽  
pp. 649-658
Author(s):  
A. Monsia ◽  
G.S.B. Mègnigbèto ◽  
D. Gnanvossou ◽  
M.F. Karlsson
Keyword(s):  
Biological Control ◽  
Associative Learning ◽  
Fruit Fly ◽  
Bactrocera Dorsalis ◽  
Pest Species ◽  
Fopius Arisanus ◽  
Host Fruit ◽  
Control Programmes ◽  
Odour Learning ◽  
Ceratitis Cosyra

AbstractParasitoids, released in augmentative biological control programmes, which display a rapid host-location capacity, have a higher likelihood of successfully controlling target pest species. By learning to associate sensory cues to a suitable oviposition site, might parasitoids used as biological control agents, locate hosts more rapidly, and perhaps increase the efficacity of e.g. Tephritidae fruit fly management. We studied associative learning of Fopius arisanus (Hymenoptera: Braconidae) and tested its range of learning in natural and conditional hosts and host fruits, i.e. Bactrocera dorsalis, Zeugodacus cucurbitae, Ceratitis capitata and Ceratitis cosyra (Diptera: Tephritidae) and on fruits (papaya, tomato, banana). Naïve female F. arisanus were compared with experienced wasps, which had been offered infested and non-infested fruit, and been allowed to oviposit. Preferences for olfactory cues from infested fruits were thereafter assessed in a two-choice olfactometer. Naïve and trained parasitoids preference differed in general and non-responders to infested fruits were higher among naïve parasitoids. The trained wasps preferred the fruit infested in the training more than the control fruit, for all combination, except when C. cosyra infested the fruits, hence avoidance behavioural response was observed towards the odour of the infested fruit. Fopius arisanus was capable of behaviourally respond to the learned information, e.g. associative odour learning was achieved, yet limited depending on interaction level, fruit fly and fruit combination. To create F. arisanus preference of an associated odour, it might hence be needed to ensure oviposition in perceived suitable host and host fruit, for the parasitoid learning to become favourable in a biological control setup.

scholarly journals The ALK-1/SMAD/ATOH8 axis attenuates hypoxic responses and protects against the development of pulmonary arterial hypertension

2019 ◽  
Vol 12 (607) ◽  
pp. eaay4430 ◽  
Author(s):  
Masato Morikawa ◽  
Yoshihide Mitani ◽  
Katarina Holmborn ◽  
Taichi Kato ◽  
Daizo Koinuma ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Vascular Diseases ◽  
Bmp Signaling ◽  
Morphogenetic Protein ◽  
Pulmonary Arterial ◽  
Direct Target ◽  
Deficient Mice

Dysregulated bone morphogenetic protein (BMP) signaling in endothelial cells (ECs) is implicated in vascular diseases such as pulmonary arterial hypertension (PAH). Here, we showed that the transcription factor ATOH8 was a direct target of SMAD1/5 and was induced in a manner dependent on BMP but independent of Notch, another critical signaling pathway in ECs. In zebrafish and mice, inactivation of Atoh8 did not cause an arteriovenous malformation–like phenotype, which may arise because of dysregulated Notch signaling. In contrast, Atoh8-deficient mice exhibited a phenotype mimicking PAH, which included increased pulmonary arterial pressure and right ventricular hypertrophy. Moreover, ATOH8 expression was decreased in PAH patient lungs. We showed that in cells, ATOH8 interacted with hypoxia-inducible factor 2α (HIF-2α) and decreased its abundance, leading to reduced induction of HIF-2α target genes in response to hypoxia. Together, these findings suggest that the BMP receptor type II/ALK-1/SMAD/ATOH8 axis may attenuate hypoxic responses in ECs in the pulmonary circulation and may help prevent the development of PAH.

scholarly journals Comprehensive genomic screens identify a role for PLZF-RARα as a positive regulator of cell proliferation via direct regulation of c-MYC

Blood ◽  
2009 ◽  
Vol 114 (27) ◽  
pp. 5499-5511 ◽  
Author(s):  
Kim L. Rice ◽  
Itsaso Hormaeche ◽  
Sergei Doulatov ◽  
Jared M. Flatow ◽  
David Grimwade ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Dominant Negative ◽  
Myeloid Leukemias ◽  
Direct Target ◽  
Retinoic Acid Receptor Α ◽  
Chip Chip

Abstract The t(11;17)(q23;q21) translocation is associated with a retinoic acid (RA)–insensitive form of acute promyelocytic leukemia (APL), involving the production of reciprocal fusion proteins, promyelocytic leukemia zinc finger–retinoic acid receptor α (PLZF-RARα) and RARα-PLZF. Using a combination of chromatin immunoprecipitation promotor arrays (ChIP-chip) and gene expression profiling, we identify novel, direct target genes of PLZF-RARα that tend to be repressed in APL compared with other myeloid leukemias, supporting the role of PLZF-RARα as an aberrant repressor in APL. In primary murine hematopoietic progenitors, PLZF-RARα promotes cell growth, and represses Dusp6 and Cdkn2d, while inducing c-Myc expression, consistent with its role in leukemogenesis. PLZF-RARα binds to a region of the c-MYC promoter overlapping a functional PLZF site and antagonizes PLZF-mediated repression, suggesting that PLZF-RARα may act as a dominant-negative version of PLZF by affecting the regulation of shared targets. RA induced the differentiation of PLZF-RARα–transformed murine hematopoietic cells and reduced the frequency of clonogenic progenitors, concomitant with c-Myc down-regulation. Surviving RA-treated cells retained the ability to be replated and this was associated with sustained c-Myc expression and repression of Dusp6, suggesting a role for these genes in maintaining a self-renewal pathway triggered by PLZF-RARα.

FRACTAL DIMENSION OF THE DROSOPHILA CIRCADIAN CLOCK

Fractals ◽  
2011 ◽  
Vol 19 (04) ◽  
pp. 423-430 ◽  
Author(s):  
HASSAN M. FATHALLAH-SHAYKH
Keyword(s):  
Fractal Dimension ◽  
Circadian Clock ◽  
Lyapunov Exponents ◽  
Fractal Geometry ◽  
Target Genes ◽  
Transcriptional Repressor ◽  
High Dimensional ◽  
Counting Procedure ◽  
Box Counting ◽  
Direct Target

Fractal geometry can adequately represent many complex and irregular objects in nature. The fractal dimension is typically computed by the box-counting procedure. Here I compute the box-counting and the Kaplan-Yorke dimensions of the 14-dimensional models of the Drosophila circadian clock. Clockwork Orange (CWO) is transcriptional repressor of direct target genes that appears to play a key role in controlling the dynamics of the clock. The findings identify these models as strange attractors and highlight the complexity of the time-keeping actions of CWO in light-day cycles. These fractals are high-dimensional counterexamples of the Kaplan-Yorke conjecture that uses the spectrum of the Lyapunov exponents.

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