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The E-protein Daughterless regulates protein translation and memory in adult Drosophila nervous system

ABSTRACT: Daughterless (Da), the Drosophila melanogaster homolog of mammalian E-protein transcription factor 4 (TCF4), is well studied in fruit fly embryonic development but its functions in adult nervous system are poorly understood. Mutations in human TCF4 gene lead to intellectual disabilities such as Pitt-Hopkins syndrome and TCF4 has also been linked to schizophrenia. Here, to explore the roles of Da in the Drosophila mature brain, we map Da DNA binding sites and study the transcriptomics of the brains where Da function is inhibited by pan-neuronal Extramacrohaete (Emc) overexpression, in both male and female Drosophila Our transcriptome analyses reveal that in the adult brain Da regulates the expression of genes involved in behavior, memory, synaptic signaling, protein translation, and metabolic processes. Moreover, combining the RNA sequencing data with Da ChIP sequencing results indicates that genes associated with neuronal projection guidance, metabolism, and translation are direct targets of Da. In addition, we validate the involvement of Da in memory formation. Overall, our results provide valuable information about the functions of Da in the adult brain and aid in better understanding the mechanisms of TCF4-related disorders.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE279107 | GEO | 2026/01/27

REPOSITORIES: GEO

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The E-protein Daughterless regulates protein translation and memory in adult Drosophila nervous system [RNA-seq]

Project description:Daughterless (Da), the Drosophila melanogaster homolog of mammalian E-protein transcription factor 4 (TCF4), is well studied in fruit fly embryonic development but its functions in adult nervous system are poorly understood. Mutations in human TCF4 gene lead to intellectual disabilities such as Pitt-Hopkins syndrome and TCF4 has also been linked to schizophrenia. Here, to explore the roles of Da in the Drosophila mature brain, we map Da DNA binding sites and study the transcriptomics of the brains where Da function is inhibited by pan-neuronal Extramacrohaete (Emc) overexpression, in both male and female Drosophila Our transcriptome analyses reveal that in the adult brain Da regulates the expression of genes involved in behavior, memory, synaptic signaling, protein translation, and metabolic processes. Moreover, combining the RNA sequencing data with Da ChIP sequencing results indicates that genes associated with neuronal projection guidance, metabolism, and translation are direct targets of Da. In addition, we validate the involvement of Da in memory formation. Overall, our results provide valuable information about the functions of Da in the adult brain and aid in better understanding the mechanisms of TCF4-related disorders.

2026-01-27 | GSE279158 | GEO

Patient-derived brain organoids uncover reversible cellular abnormalities in Pitt-Hopkins Syndrome III

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Patient-derived brain organoids uncover reversible cellular abnormalities in Pitt-Hopkins Syndrome II

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Patient-derived brain organoids uncover reversible cellular abnormalities in Pitt-Hopkins Syndrome

2022-03-02 | GSE159392 | GEO

Patient-derived brain organoids uncover reversible cellular abnormalities in Pitt-Hopkins Syndrome IV

2022-03-02 | GSE189121 | GEO

Knockdown of the schizophrenia susceptibility gene TCF4 alters gene expression and proliferation of progenitor cells from the developing human neocortex.

Project description:BACKGROUND: Common variants in the TCF4 gene are among the most robustly supported genetic risk factors for schizophrenia. Rare TCF4 deletions and loss-of-function point mutations cause Pitt-Hopkins syndrome, a developmental disorder associated with severe intellectual disability. METHODS: In order to explore molecular and cellular mechanisms by which TCF4 perturbation could interfere with human cortical development, we experimentally reduced the endogenous expression of TCF4 in a neural progenitor cell line derived from the developing human cerebral cortex using RNA interference. Effects on genome-wide gene expression were assessed by microarray, followed by Gene Ontology and pathway analysis of differentially expressed genes. Effects on cell proliferation were assessed using high content imaging. RESULTS: Genes that were differentially expressed following TCF4 knockdown were highly enriched for involvement in the cell cycle. Consistent with the gene expression data, TCF4 knockdown was associated with reduced proliferation of cortical progenitor cells in vitro. CONCLUSIONS: Our data indicate effects of TCF4 perturbation on human cortical progenitor cell proliferation, a process that could contribute to cognitive deficits in Pitt-Hopkins Syndrome and risk for schizophrenia.

2016-10-01 | GSE62085 | GEO

TCF4 regulatory gene networks in developing dorsal telencephalon

Project description:Haplo-insufficiency of TCF4 induced by mutations or microdeletion of TCF4 gene causes Pitt-Hopkins Diseases. Recent gene association studies revealed that mutations of TCF4 is significantly associated with schizophrenia. But the role of TCF4 in developing neocortex is not known. The goal of this study is to identify TCF4 itranscriptional regulatory pathways in developing neocortex by analyzing transcriptomes of dorsal telencephalons of TCF4knockout, TCF4Heterozygote and WT littermates and comparing differential expressed genes between these genotypes.

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Transcription factor 4 controls positioning of cortical projection neurons through regulation of cell adhesion

Project description:The establishment of neural circuits depends on precise neuronal positioning in the cortex, a tightly coordinated process of neuronal differentiation, migration and terminal localization. Deficit in this process is implicated in several psychiatric disorders. Here, we show that the transcription factor Tcf4 controls neuronal positioning during brain development. Tcf4-deficient neurons become mispositioned in clusters when their migration to the cortical plate is complete. We reveal that Tcf4 regulates the expression of cell adhesion molecules to control neuronal positioning. Furthermore, through in vivo extracellular electrophysiology, we show that neuronal functions are disrupted after the loss of Tcf4. TCF4 mutations are strongly associated with schizophrenia and cause Pitt-Hopkins syndrome, which is characterized by severe intellectual disability. Thus, our results not only reveal the importance of neuronal positioning in brain development and but also provide new insights into the potential mechanisms underlying neurological defects linked to TCF4 mutations.

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scRNA sequencing uncovers a TCF4-dependent transcription factor network regulating commissure development in mouse

Project description:The bHLH transcription factor TCF4 plays an important role in neurodevelopment highlighted by its association with schizophrenia and Pitt-Hopkins-Syndrome. Here we demonstrate that TCF4 function is essential for forebrain commissure formation in mice. Single-cell RNA sequencing of TCF4 knockout neocortices revealed dysregulation of multiple gene regulatory networks. We provide evidence that TCF4 controls the underlying regulons by interaction with the regulators, transcription factors surprisingly not belonging to the known canonical interactors of the bHLH family. In-depth analysis of the interplay between TCF4 and SOX11 showed a synergistic effect on commissural formation. Mice haploinsufficient for Sox11 or Tcf4 showed no commissural phenotype or only a mild callosal shortening, respectively, whereas Tcf4/Sox11 double haploinsufficient mice display aggravated corpus callosum dysgenesis and anterior commissure agenesis. Moreover, TCF4 and SOX11 synergistically induce the expression of common target genes. Collectively, these findings illuminate how TCF4 dysregulation influences brain development and contributes to neurodevelopmental diseases.

2021-07-04 | GSE147247 | GEO

Transcription factor 4 regulates the interhemispheric midline remodeling through neuron–astroglia communications during corpus callosum formation

Project description:Agenesis of the corpus callosum (CC), the largest axon tract bridging the two hemispheres of the brain to support higher cognitive functions, is linked to various neurological disorders, including intellectual disability and autism spectrum disorders. Mutations of the transcription factor 4 (TCF4) cause Pitt-Hopkins Syndrome, an autism spectrum brain disorder characterized by severe intellectual disability. Through ex vivo transplantation assays and pioneering single-cell RNA sequencing of the interhemispheric midline, we found that Tcf4-mediated neuron-astroglia communication is essential for establishing the midline structure and subsequent CC formation. Conditional inactivation of Tcf4 in guidepost neurons disrupts astroglia functions and impedes interhemispheric fissure closure, thereby preventing axonal crossing of callosal projection neurons to the contralateral cortex. Moreover, we identified Sema7A as a key mediator of neuron-astroglia communications. Therefore, our study reveals a crucial, previously unappreciated role of cell-cell communication in interhemispheric midline remodeling, providing novel insights into the potential mechanisms underlying TCF4 associated neurological disorders.

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