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.

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 Basic Helix-Loop-Helix (bHLH) Transcription Factors Regulate a Wide Range of Functions in Arabidopsis

2021 ◽  
Vol 22 (13) ◽  
pp. 7152
Author(s):  
Yaqi Hao ◽  
Xiumei Zong ◽  
Pan Ren ◽  
Yuqi Qian ◽  
Aigen Fu
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Target Genes ◽  
Gene Families ◽  
Bhlh Transcription Factor ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Wide Range ◽  
Range Of Functions ◽  
Eukaryotic Organisms

The basic helix-loop-helix (bHLH) transcription factor family is one of the largest transcription factor gene families in Arabidopsis thaliana, and contains a bHLH motif that is highly conserved throughout eukaryotic organisms. Members of this family have two conserved motifs, a basic DNA binding region and a helix-loop-helix (HLH) region. These proteins containing bHLH domain usually act as homo- or heterodimers to regulate the expression of their target genes, which are involved in many physiological processes and have a broad range of functions in biosynthesis, metabolism and transduction of plant hormones. Although there are a number of articles on different aspects to provide detailed information on this family in plants, an overall summary is not available. In this review, we summarize various aspects of related studies that provide an overview of insights into the pleiotropic regulatory roles of these transcription factors in plant growth and development, stress response, biochemical functions and the web of signaling networks. We then provide an overview of the functional profile of the bHLH family and the regulatory mechanisms of other proteins.

Mef2C Is a Lineage-Restricted Target Gene of Scl/Tal1 and Regulates Megakaryopoiesis and B-Cell Homeostasis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 278-278
Author(s):  
Katrin E Rhodes ◽  
Christos Gekas ◽  
Laurraine Gereige ◽  
Hildur Helgadottir ◽  
Roberto Ferrari ◽  
...  
Keyword(s):  
Transcription Factor ◽  
B Cell ◽  
Muscle Development ◽  
Target Genes ◽  
Fetal Liver ◽  
Premature Aging ◽  
Bhlh Transcription Factor ◽  
Functional Requirements ◽  
B Lymphoid ◽  
Deficient Mice

Abstract The bHLH transcription factor stem cell leukemia/T-cell acute leukemia gene (Scl/Tal1) is a master regulator for hematopoiesis, essential for hematopoietic specification and proper differentiation of the erythroid and megakaryocyte lineages. However, the critical downstream targets of Scl remain undefined. To identify Scl target genes in hematopoietic cells, we performed gene expression analysis on HOX11-immortalized Sclfl/fl fetal liver cell lines. Analysis of the top 50 downregulated genes revealed several genes related to hematopoiesis including erythroid and megakaryocyte development, vasculogenesis, as well as genes/unknown ESTs that have not been previously linked to blood development. One of the top downregulated genes was transcription factor myocyte enhancer factor 2C (Mef2C). Mef2C−/− embryos die at E9.5, the same time as Scl−/− embryos, and exhibit severe defects in cardiac and muscle development. Analysis of Mef2C−/− embryos showed that, Mef2C, in contrast to Scl, is not required for specification into primitive or definitive hematopoietic lineages. To bypass the embryonic lethality, we utilized a conditionally targeted Mef2Cfl/fl strain and crossed it with a hematopoietic cell-specific VavCre strain that deactivates Mef2C shortly after the emergence of HSCs. Interestingly, adult VavCre+Mef2Cfl/fl mice exhibited severe platelet defects highly reminiscent to those observed in Scl deficient mice. The platelet counts were reduced, while platelet size was increased and the platelet shape and granularity was altered. Furthermore, megakaryopoiesis was severely impaired in vitro. ChIP-on-chip analysis revealed that Mef2C is directly regulated by Scl in megakaryocytic cells, but not in erythroid cells. In addition, an Scl independent requirement for Mef2C in B-lymphoid homeostasis was observed in Mef2C-deficient mice, characterized as severe age-dependent reductions of specific B-cell progenitor populations reminiscent of premature aging. In summary, this work identifies Mef2C as an integral member of hematopoietic transcription factors with distinct upstream regulatory mechanisms and functional requirements in megakaryocyte and B-lymphoid lineages.

A novel fibroblast growth factor gene expressed in the developing nervous system is a downstream target of the chimeric homeodomain oncoprotein E2A-Pbx1

Development ◽  
1997 ◽  
Vol 124 (17) ◽  
pp. 3221-3232 ◽  
Author(s):  
J.R. McWhirter ◽  
M. Goulding ◽  
J.A. Weiner ◽  
J. Chun ◽  
C. Murre
Keyword(s):  
Nervous System ◽  
Transcription Factor ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Target Genes ◽  
Representational Difference Analysis ◽  
Bhlh Transcription Factor ◽  
Fibroblast Growth ◽  
Downstream Target ◽  
Developing Nervous System

Pbx1 is a homeodomain transcription factor that has the ability to form heterodimers with homeodomain proteins encoded by the homeotic selector (Hox) gene complexes and increase their DNA-binding affinity and specificity. A current hypothesis proposes that interactions with Pbx1 are necessary for Hox proteins to regulate downstream target genes that in turn control growth, differentiation and morphogenesis during development. In pre B cell leukemias containing the t(1;19) chromosome translocation, Pbx1 is converted into a strong transactivator by fusion to the activation domain of the bHLH transcription factor E2A. The E2A-Pbx1 fusion protein should therefore activate transcription of genes normally regulated by Pbx1. We have used the subtractive process of representational difference analysis to identify targets of E2A-Pbx1. We show that E2A-Pbx1 can directly activate transcription of a novel member of the fibroblast growth factor family of intercellular signalling molecules, FGF-15. The FGF-15 gene is expressed in a regionally restricted pattern in the developing nervous system, suggesting that FGF-15 may play an important role in regulating cell division and patterning within specific regions of the embryonic brain, spinal cord and sensory organs.

Dual role of the basic helix-loop-helix transcription factor scleraxis in mesoderm formation and chondrogenesis during mouse embryogenesis

Development ◽  
1999 ◽  
Vol 126 (19) ◽  
pp. 4317-4329 ◽  
Author(s):  
D. Brown ◽  
D. Wagner ◽  
X. Li ◽  
J.A. Richardson ◽  
E.N. Olson
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
Embryonic Stem ◽  
Primitive Streak ◽  
Axial Skeleton ◽  
Bhlh Transcription Factor ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Mesoderm Formation ◽  
Cell Layers

Scleraxis is a basic helix-loop-helix (bHLH) transcription factor shown previously to be expressed in developing chondrogenic cell lineages during embryogenesis. To investigate its function in embryonic development, we produced scleraxis-null mice by gene targeting. Homozygous mutant embryos developed normally until the early egg cylinder stage (embryonic day 6.0), when they became growth-arrested and failed to gastrulate. Consistent with this early embryonic phenotype, scleraxis was found to be expressed throughout the embryo at the time of gastrulation before becoming restricted to chondrogenic precursor cells at embryonic day 9.5. At the time of developmental arrest, scleraxis-null embryos consisted of ectodermal and primitive endodermal cell layers, but lacked a primitive streak or recognizable mesoderm. Analysis of molecular markers of the three embryonic germ layers confirmed that scleraxis mutant embryos were unable to form mesoderm. By generating chimeric embryos, using lacZ-marked scleraxis-null and wild-type embryonic stem cells, we examined the ability of mutant cells to contribute to regions of the embryo beyond the time of lethality of homozygous mutants. Scleraxis-null cells were specifically excluded from the sclerotomal compartment of somites, which gives rise to the axial skeleton, and from developing ribs, but were able to contribute to most other regions of the embryo, including mesoderm-derived tissues. These results reveal an essential early role for scleraxis in mesoderm formation, as well as a later role in formation of somite-derived chondrogenic lineages, and suggest that scleraxis target genes mediate these processes.

scholarly journals TRANSPARENT TESTA GLABRA1, a Key Regulator in Plants with Multiple Roles and Multiple Function Mechanisms

2020 ◽  
Vol 21 (14) ◽  
pp. 4881 ◽  
Author(s):  
Hainan Tian ◽  
Shucai Wang
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Target Genes ◽  
Multiple Roles ◽  
26S Proteasome ◽  
Bhlh Transcription Factor ◽  
Transcription Activator ◽  
Downstream Target ◽  
Transparent Testa ◽  
Functional Mechanisms

TRANSPARENT TESTA GLABRA1 (TTG1) is a WD40 repeat protein. The phenotypes caused by loss-of-function of TTG1 were observed about half a century ago, but the TTG1 gene was identified only about twenty years ago. Since then, TTG1 has been found to be a plant-specific regulator with multiple roles and multiple functional mechanisms. TTG1 is involved in the regulation of cell fate determination, secondary metabolisms, accumulation of seed storage reserves, plant responses to biotic and abiotic stresses, and flowering time in plants. In some processes, TTG1 may directly or indirectly regulate the expression of downstream target genes via forming transcription activator complexes with R2R3 MYB and bHLH transcription factors. Whereas in other processes, TTG1 may function alone or interact with other proteins to regulate downstream target genes. On the other hand, the studies on the regulation of TTG1 are very limited. So far, only the B3-domain family transcription factor FUSCA3 (FUS3) has been found to regulate the expression of TTG1, phosphorylation of TTG1 affects its interaction with bHLH transcription factor TT2, and TTG1 proteins can be targeted for degradation by the 26S proteasome. Here, we provide an overview of TTG1, including the identification of TTG1, the functions of TTG1, the possible function mechanisms of TTG1, and the regulation of TTG1. We also proposed potential research directions that may shed new light on the regulation and functional mechanisms of TTG1 in plants.

scholarly journals The Oncogenic Function of PLAGL2 is Mediated via Specific Target Genes Through a Wnt-independent Mechanism in Colorectal Cancer

2020 ◽  
Author(s):  
Anthony D. Fischer ◽  
Daniel A. Veronese-Paniagua ◽  
Shriya Swaminathan ◽  
Hajime Kashima ◽  
Deborah C. Rubin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Transcription Factor ◽  
Stem Cell ◽  
Wnt Signaling ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Bhlh Transcription Factor ◽  
Cycle Progression

ABSTRACTColorectal cancer (CRC) tumorigenesis and progression are linked to common oncogenic mutations, especially in the tumor suppressor APC, whose loss triggers the deregulation of TCF4/β-Catenin activity. CRC tumorigenesis is also driven by multiple epi-mutational modifiers, such as transcriptional regulators. We describe the common (and near-universal) activation of the zinc finger transcription factor and Let-7 target PLAGL2 in CRC and find that it is a key driver of intestinal epithelial transformation. PLAGL2 drives proliferation, cell cycle progression, and anchorage-independent growth in CRC cell lines and non-transformed intestinal cells. Investigating effects of PLAGL2 on downstream pathways revealed very modest effects on canonical Wnt signaling. Alternatively, we find pronounced effects on the direct PLAGL2 target genes IGF2, a fetal growth factor, and ASCL2, an intestinal stem cell-specific bHLH transcription factor. Inactivation of PLAGL2 in CRC cell lines has pronounced effects on ASCL2 reporter activity. Furthermore, ASCL2 expression can partially rescue deficits of proliferation and cell cycle progression caused by depletion of PLAGL2 in CRC cell lines. Thus, the oncogenic effects of PLAGL2 appear to be mediated via core stem cell and onco-fetal pathways, with minimal effects on downstream Wnt signaling.

The bHLH transcription factor dHAND controls Sonic hedgehog expression and establishment of the zone of polarizing activity during limb development

Development ◽  
2000 ◽  
Vol 127 (11) ◽  
pp. 2461-2470 ◽  
Author(s):  
J. Charite ◽  
D.G. McFadden ◽  
E.N. Olson
Keyword(s):  
Transcription Factor ◽  
Sonic Hedgehog ◽  
Limb Development ◽  
Target Genes ◽  
Ectopic Expression ◽  
Tissue Growth ◽  
Limb Bud ◽  
Bhlh Transcription Factor ◽  
Expression Domain ◽  
Zone Of Polarizing Activity

Limb outgrowth and patterning of skeletal elements are dependent on complex tissue interactions involving the zone of polarizing activity (ZPA) in the posterior region of the limb bud and the apical ectodermal ridge. The peptide morphogen Sonic hedgehog (SHH) is expressed specifically in the ZPA and, when expressed ectopically, is sufficient to mimic its functions, inducing tissue growth and formation of posterior skeletal elements. We show that the basic helix-loop-helix transcription factor dHAND is expressed posteriorly in the developing limb prior to Shh and subsequently occupies a broad domain that encompasses the Shh expression domain. In mouse embryos homozygous for a dHAND null allele, limb buds are severely underdeveloped and Shh is not expressed. Conversely, misexpression of dHAND in the anterior region of the limb bud of transgenic mice results in formation of an additional ZPA, revealed by ectopic expression of Shh and its target genes, and resulting limb abnormalities that include preaxial polydactyly with duplication of posterior skeletal elements. Analysis of mouse mutants in which Hedgehog expression is altered also revealed a feedback mechanism in which Hedgehog signaling is required to maintain the full dHAND expression domain in the developing limb. Together, these findings identify dHAND as an upstream activator of Shh expression and important transcriptional regulator of limb development.

scholarly journals midline represses Dpp signaling and target gene expression in Drosophila ventral leg development

2021 ◽  
Author(s):  
Lindsay A. Phillips ◽  
Markle L. Atienza ◽  
Jae-Ryeon Ryu ◽  
Pia C. Svendsen ◽  
Lynn K. Kelemen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Dna Sequence ◽  
Target Gene ◽  
Target Genes ◽  
T Box ◽  
Leg Development ◽  
Summary Statement

AbstractVentral leg patterning in Drosophila is controlled by the expression of the redundant T-box Transcription factors midline (mid) and H15. Here we show that mid represses the Dpp-activated gene Daughters against decapentaplegic (Dad) through a consensus TBE site in the minimal enhancer, Dad13. Mutating the Dad13 DNA sequence results in an increased and broadening of Dad expression. We further demonstrate that the engrailed-homology-1 domain of Mid is critical for regulating the levels of phospho-Mad, a transducer of Dpp-signaling. However, we find that mid does not affect all Dpp-target genes as we demonstrate that brinker (brk) expression is unresponsive to mid. This study further illuminates the interplay between mechanisms involved in determination of cellular fate and the varied roles of mid.Summary statementVentral patterning is controlled in part by the T-box Transcription factor midline blocking Dpp signaling and Dpp-activated genes, though midline does not affect the Dpp-repressed gene brk.

scholarly journals scRNA-Sequencing uncovers a TCF4-dependent transcription factor network regulating commissure development

Development ◽  
2021 ◽  
Author(s):  
Marie-Theres Wittmann ◽  
Sayako Katada ◽  
Elisabeth Sock ◽  
Philipp Kirchner ◽  
Arif B. Ekici ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Activity ◽  
Projection Neurons ◽  
Bhlh Transcription Factor ◽  
Sequencing Data ◽  
Functional Interaction ◽  
Interhemispheric Connectivity ◽  
Identify Transcription Factor ◽  
Transcription Factor 4

Transcription factor 4 (TCF4) is a critical regulator of neurodevelopment and has been linked to the pathogenesis of autism, intellectual disability, and schizophrenia. As a class I bHLH transcription factor it is assumed that TCF4 exerts its neurodevelopmental functions through dimerization with proneural class II bHLH TFs. Here, we aim to identify transcription factor (TF) partners of TCF4 in the control of interhemispheric connectivity formation. Using a new bioinformatic strategy integrating TF expression levels and regulon activities from single cell RNA-sequencing data, we find evidence that TCF4 interacts with non-bHLH TFs and modulates their transcriptional activity in Satb2+ intercortical projection neurons. Notably, this network comprises regulators linked to the pathogenesis of neurodevelopmental disorders, e.g. FOXG1, SOX11 and BRG1. In support of the functional interaction of TCF4 with non-bHLH TFs we find that TCF4 and SOX11 biochemically interact and cooperatively control commissure formation in vivo, and regulate the transcription of genes implied in this process. Next to identifying new candidate interactors of TCF4 in neurodevelopment, this study illustrates how scRNA-Seq data can be leveraged to predict TFs networks in neurodevelopmental processes.

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