Abstract
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.
Highlights
Transcription factor 4 (TCF4, known as ITF2, E2-2, SEF2, etc.) belongs to the family of class I basic helix-loop-helix transcription factors, called E-proteins (Murre et al, 1994)
We have previously demonstrated that transcription factor 4 (TCF4) function can be modelled in Drosophila melanogaster using its orthologue and the sole E-protein in the fruit fly, Daughterless (Da) (Tamberg et al, 2015)
We showed that Da is broadly expressed in the larval central nervous system (CNS), including in populations of Kenyon cells contributing to the mushroom body, which is the memory and learning centre of insects
Summary
Transcription factor 4 (TCF4, known as ITF2, E2-2, SEF2, etc.) belongs to the family of class I basic helix-loop-helix (bHLH) transcription factors, called E-proteins (Murre et al, 1994). E-proteins bind to the DNA Ephrussi box (E-box) sequence CANNTG as homodimers or heterodimers with class II bHLH transcription factors (Cabrera and Alonso, 1991). TCF4 should be distinguished from TCF7L2, a downstream effector of the Wnt signalling pathway that is referred to as TCF4 (T cell factor 4). Genes involved in pathways including nervous system development, synaptic function and axon development are TCF4 targets (Forrest et al, 2018; Xia et al, 2018). Recent insights into the mechanisms of activation of TCF4 show that TCF4-dependent transcription in primary neurons is induced by neuronal activity via soluble adenylyl cyclase and protein kinase A (PKA) signalling (Sepp et al, 2017). In addition to the nervous system, TCF4 has been shown to function in the immune system during the development of plasmacytoid dendritic cells (Cisse et al, 2008; Grajkowska et al, 2017)
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