Date Published: February 12, 2019
Publisher: Public Library of Science
Author(s): Anna Castells-Nobau, Ilse Eidhof, Michaela Fenckova, Dova B. Brenman-Suttner, Jolanda M. Scheffer-de Gooyert, Sheren Christine, Rosa L. Schellevis, Kiran van der Laan, Christine Quentin, Lisa van Ninhuijs, Falko Hofmann, Radoslaw Ejsmont, Simon E. Fisher, Jamie M. Kramer, Stephan J. Sigrist, Anne F. Simon, Annette Schenck, Gaiti Hasan.
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.
The forkhead box P (FOXP) transcription factors form a subfamily of evolutionarily conserved proteins. In mammals, the subfamily consists of four members, FOXP1-4, which have a wide range of important biological functions. FOXP1, FOXP2 and FOXP4 are highly homologous, present partially overlapping expression patterns in vertebrate brains [1, 2] and are involved, amongst other tissues, in the development and functioning of the central nervous system (CNS) . FOXP3, evolutionarily the most distal member of the subfamily, is known for its expression and function in the immune system .
In this study, we show that Drosophila FoxP is specifically expressed in about 1000 neurons in the adult brain and is required for many aspects of neural development, including synaptic morphogenesis at the NMJ, dendrite development of type IV multidendritic neurons and formation of MB α-lobes in the central brain. We also show that FoxP modulates normal locomotion and more complex behaviors such as habituation and social space. We report that Drosophila FoxP presents shared properties with its vertebrate orthologues including the conservation of protein domains and dimerization, and evolutionarily conserved functional properties in the CNS.