Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of the synaptic proteome
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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2020-07-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/13/7/dmm042747 |
| _version_ | 1811333301860827136 |
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| author | Laura Tamberg Mariliis Jaago Kristi Säälik Alex Sirp Jürgen Tuvikene Anastassia Shubina Carl Sander Kiir Kaja Nurm Mari Sepp Tõnis Timmusk Mari Palgi |
| author_facet | Laura Tamberg Mariliis Jaago Kristi Säälik Alex Sirp Jürgen Tuvikene Anastassia Shubina Carl Sander Kiir Kaja Nurm Mari Sepp Tõnis Timmusk Mari Palgi |
| author_sort | Laura Tamberg |
| collection | DOAJ |
| description | 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. This article has an associated First Person interview with the first author of the paper. |
| first_indexed | 2024-04-13T16:50:39Z |
| format | Article |
| id | doaj.art-e9eb23f915e44512bcbe5dbd46a224f3 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-04-13T16:50:39Z |
| publishDate | 2020-07-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-e9eb23f915e44512bcbe5dbd46a224f32022-12-22T02:38:57ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112020-07-0113710.1242/dmm.042747042747Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of the synaptic proteomeLaura Tamberg0Mariliis Jaago1Kristi Säälik2Alex Sirp3Jürgen Tuvikene4Anastassia Shubina5Carl Sander Kiir6Kaja Nurm7Mari Sepp8Tõnis Timmusk9Mari Palgi10 Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia 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. This article has an associated First Person interview with the first author of the paper.http://dmm.biologists.org/content/13/7/dmm042747tcf4daughterlesspitt–hopkins syndromeintellectual disabilitydrosophila melanogasterappetitive associative learningnegative geotaxis |
| spellingShingle | Laura Tamberg Mariliis Jaago Kristi Säälik Alex Sirp Jürgen Tuvikene Anastassia Shubina Carl Sander Kiir Kaja Nurm Mari Sepp Tõnis Timmusk Mari Palgi Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of the synaptic proteome Disease Models & Mechanisms tcf4 daughterless pitt–hopkins syndrome intellectual disability drosophila melanogaster appetitive associative learning negative geotaxis |
| title | Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of the synaptic proteome |
| title_full | Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of the synaptic proteome |
| title_fullStr | Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of the synaptic proteome |
| title_full_unstemmed | Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of the synaptic proteome |
| title_short | Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of the synaptic proteome |
| title_sort | daughterless the drosophila orthologue of tcf4 is required for associative learning and maintenance of the synaptic proteome |
| topic | tcf4 daughterless pitt–hopkins syndrome intellectual disability drosophila melanogaster appetitive associative learning negative geotaxis |
| url | http://dmm.biologists.org/content/13/7/dmm042747 |
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