成体ショウジョウバエの嗅覚学習を調節するEタンパク質Daughterless

Daughterless (Da), the Drosophila melanogaster homolog of mammalian 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 lead to intellectual disabilities such as Pitt-Hopkins syndrome (PTHS) and TCF4 has also been linked to schizophrenia. Here, to explore the roles of Da in 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 behaviour, memory, synaptic signaling, protein translation and metabolic processes. Moreover, combining the RNA-sequencing data with Da ChIP-seq 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.Significance Statement Daughterless (Da), the Drosophila melanogaster homolog for mammalian E-proteins TCF4, TCF3 and TCF12, is a basic-helix-loop-helix transcription factor known for its roles during nervous system development. We have previously shown that Da is expressed in the adult Drosophila brain but little is known of its functions there. TCF4, a human ortholog of Da, is associated with the intellectual disability syndrome Pitt-Hopkins syndrome and schizophrenia. The molecular mechanisms of these serious conditions are largely unknown. Investigating the functions of Da in the nervous system potentially provides information about the functioning of TCF4 as well and could help in better understanding the mechanisms of the diseases associated with TCF4.