Conserved sleep disturbances in FOXP1 syndrome originate from developmental dysregulation of peptidergic signaling
Mireia Coll-Tané, Ilse Eidhof, Jie Han, Nicholas Raun, Lara V. van Renssen, Simon E. Fisher, Matthew S. Kayser, Tjitske Kleefstra, Sigrid Pillen, Caitlin M. Hudac, Jordi Mayneris-Perxachs, Marieke Klein, Saskia Koene, Anna Castells-Nobau, Annette Schenck
Mireia Coll-Tané, Ilse Eidhof, Jie Han, Nicholas Raun, Lara V. van Renssen, Simon E. Fisher, Matthew S. Kayser, Tjitske Kleefstra, Sigrid Pillen, Caitlin M. Hudac, Jordi Mayneris-Perxachs, Marieke Klein, Saskia Koene, Anna Castells-Nobau, Annette Schenck
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Research Article Clinical Research Neuroscience

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

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.

Authors

Mireia Coll-Tané, Ilse Eidhof, Jie Han, Nicholas Raun, Lara V. van Renssen, Simon E. Fisher, Matthew S. Kayser, Tjitske Kleefstra, Sigrid Pillen, Caitlin M. Hudac, Jordi Mayneris-Perxachs, Marieke Klein, Saskia Koene, Anna Castells-Nobau, Annette Schenck

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Figure 2

Common variants in FOXP1, FOXP2, and FOXP4 are associated with insomnia, frequent insomnia symptoms, and short sleep.

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Common variants in FOXP1, FOXP2, and FOXP4 are associated with insomnia,...
(A) Gene-based analyses of FOXP1, FOXP2, and FOXP4 reveal significant associations with multiple sleep traits. Dashed line indicates significance threshold of P < 0.001515 after correction for multiple testing of 11 traits and 3 genes. (B and C) Regional association plots showing association signals for frequent insomnia symptoms and short sleep at the FOXP1 locus. (D and E) Regional association plots showing association signals for frequent insomnia symptoms and insomnia at the FOXP2 locus. Data are shown as −log10(P value) for individual SNPs. The color of each marker reflects its linkage disequilibrium (r2) with the strongest associated SNP indicated as a purple diamond. The recombination rate is indicated in blue. Chr, chromosome.