期刊
DISEASE MODELS & MECHANISMS
卷 13, 期 7, 页码 -出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dmm.042747
关键词
TCF4; Daughterless; Pitt-Hopkins syndrome; Intellectual disability; Drosophila melanogaster; Appetitive associative learning; Negative geotaxis
资金
- Estonian Research Council [IUT19-18, PRG805]
- European Union through the European Regional Development Fund [2014-2020.4.01.15-0012]
- H2020-MSCA-RISE-2016 [EU734791]
- Pitt Hopkins Research Foundation [8, 21]
- Million Dollar Bike Ride Pilot Grant Program for Rare Disease Research at the University of Pennsylvania Orphan Disease Center [MDBR-16-122PHP, MDBR-17-127]
Mammalian 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.
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