Conserved sleep disturbances in FOXP1 syndrome originate from developmental dysregulation of peptidergic signaling

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Abstract
Sleep disturbances are among the most prevalent clinical features of FOXP1 syndrome, yet their nature and underlying mechanisms remain unclear. Here, we report that individuals with FOXP1 syndrome suffer from insomnia with sleep maintenance problems and early waking. Consistently, common variants in FOXP genes were associated with insomnia symptoms and short sleep. These sleep disturbances were recapitulated in Drosophila FoxP mutants, which exhibit severely fragmented and reduced sleep. FoxP loss also led to circadian arrhythmicity and impaired the plasticity of neuropeptide pigment dispersing factor–secreting (PDF-secreting) neurons in a non-cell-autonomous manner. FoxP was required during development for adult sleep integrity, particularly in peptidergic neurons. Transcriptomic analyses revealed a dysregulation of genes involved in peptidergic signaling, including hugin . FoxP was expressed in hugin + neurons (afferent to PDF-secreting neurons) during development, and its knockdown in these cells was sufficient to induce sleep fragmentation. Our findings establish an evolutionarily conserved role for FOXP proteins in the peptidergic regulation of sleep.
Funding Information
  • Radboudumc personal PhD fellowship (n/a)
  • travelling fellowship by The Company of Biologists (DMMTF1908278)
  • Radboudumc junior researcher fellowship (n/a)
  • Radboudumc junior researcher fellowship (n/a)
  • Netherlands Organisation for Scientific Research (NWO) ZonMw Veni (09150162010073)
  • Netherlands Organisation for Scientific Research (NWO) ZonMw Vidi (91718310)
  • Netherlands Organisation for Scientific Research (NWO) ZonMw Vici (09150181910022)
  • Max Planck Society (n/a)
  • Instituto de Salud Carlos III (Madrid, Spain) through the Miguel Servet Program, co-funded by the European Union under the European Social Fund ‘Investing in your future’ (CP24/00033)

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