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Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of synaptic proteome

Laura Tamberg, Mariliis Jaago, View ORCID ProfileKristi Säälik, View ORCID ProfileAnastassia Shubina, View ORCID ProfileCarl Sander Kiir, Alex Sirp, Tõnis Timmusk, View ORCID ProfileMari Palgi
doi: https://doi.org/10.1101/792796
Laura Tamberg
Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15 Tallinn, Estonia, 12618
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Mariliis Jaago
Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15 Tallinn, Estonia, 12618
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Kristi Säälik
Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15 Tallinn, Estonia, 12618
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Anastassia Shubina
Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15 Tallinn, Estonia, 12618
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  • ORCID record for Anastassia Shubina
Carl Sander Kiir
Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15 Tallinn, Estonia, 12618
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Alex Sirp
Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15 Tallinn, Estonia, 12618
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Tõnis Timmusk
Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15 Tallinn, Estonia, 12618
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Mari Palgi
Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15 Tallinn, Estonia, 12618
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  • ORCID record for Mari Palgi
  • For correspondence: mari.palgi@taltech.ee
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Abstract

Mammalian Transcription Factor 4 (TCF4) has been linked to schizophrenia and intellectual disabilities like Pitt-Hopkins syndrome (PTHS). Here we show that similarly to mammalian TCF4, fruit fly orthologue Daughterless (Da) is expressed in the Drosophila brain structures associated with learning and memory, the mushroom bodies. Furthermore, silencing of da in mushroom body neurons 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, since 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.

Summary statement Human TCF4, a bHLH transcription factor, is associated with intellectual disability and schizophrenia. Here we propose a Drosophila model for human disease studies using TCF4 orthologue in fruit fly, Daughterless.

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Posted October 08, 2019.
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Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of synaptic proteome
Laura Tamberg, Mariliis Jaago, Kristi Säälik, Anastassia Shubina, Carl Sander Kiir, Alex Sirp, Tõnis Timmusk, Mari Palgi
bioRxiv 792796; doi: https://doi.org/10.1101/792796
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Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of synaptic proteome
Laura Tamberg, Mariliis Jaago, Kristi Säälik, Anastassia Shubina, Carl Sander Kiir, Alex Sirp, Tõnis Timmusk, Mari Palgi
bioRxiv 792796; doi: https://doi.org/10.1101/792796

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