Conserved regulation of neurodevelopmental processes and behavior by FoxP in Drosophila

PLoS One. 2019 Feb 12;14(2):e0211652. doi: 10.1371/journal.pone.0211652. eCollection 2019.

Abstract

FOXP proteins form a subfamily of evolutionarily conserved transcription factors involved in the development and functioning of several tissues, including the central nervous system. In humans, mutations in FOXP1 and FOXP2 have been implicated in cognitive deficits including intellectual disability and speech disorders. Drosophila exhibits a single ortholog, called FoxP, but due to a lack of characterized mutants, our understanding of the gene remains poor. Here we show that the dimerization property required for mammalian FOXP function is conserved in Drosophila. In flies, FoxP is enriched in the adult brain, showing strong expression in ~1000 neurons of cholinergic, glutamatergic and GABAergic nature. We generate Drosophila loss-of-function mutants and UAS-FoxP transgenic lines for ectopic expression, and use them to characterize FoxP function in the nervous system. At the cellular level, we demonstrate that Drosophila FoxP is required in larvae for synaptic morphogenesis at axonal terminals of the neuromuscular junction and for dendrite development of dorsal multidendritic sensory neurons. In the developing brain, we find that FoxP plays important roles in α-lobe mushroom body formation. Finally, at a behavioral level, we show that Drosophila FoxP is important for locomotion, habituation learning and social space behavior of adult flies. Our work shows that Drosophila FoxP is important for regulating several neurodevelopmental processes and behaviors that are related to human disease or vertebrate disease model phenotypes. This suggests a high degree of functional conservation with vertebrate FOXP orthologues and established flies as a model system for understanding FOXP related pathologies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Behavior, Animal
  • Brain / growth & development
  • Brain / metabolism
  • Conserved Sequence
  • Drosophila Proteins / genetics
  • Drosophila Proteins / physiology*
  • Drosophila melanogaster / growth & development*
  • Drosophila melanogaster / metabolism
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / physiology*
  • Gene Knockdown Techniques
  • Locomotion
  • Mushroom Bodies / growth & development
  • Mushroom Bodies / metabolism
  • Nervous System / growth & development*
  • Nervous System / metabolism
  • Real-Time Polymerase Chain Reaction
  • Sensory Receptor Cells / physiology
  • Two-Hybrid System Techniques

Substances

  • Drosophila Proteins
  • Forkhead Transcription Factors
  • FoxP protein, Drosophila

Grants and funding

This study was in part supported by a TOP grant from the Netherlands Organization for Scientific Research (NWO-ZonMW 912-12-109, https://www.nwo.nl/) to A.S., and by an internal Radboudumc/Donders institute junior researcher fellowship to S.E.F and A.S. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.