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 3

FoxP is required in Drosophila neurons to safeguard normal sleep duration and architecture.

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FoxP is required in Drosophila neurons to safeguard normal sleep duratio...
(A) Schematic showing domain conservation between human FOXP1, FOXP2, FOXP4 and their Drosophila ortholog, FoxP. Domains include forkhead, zinc finger (ZF), leucine zipper (LZ), and polyglutamine (Q-rich). Adapted from Castells-Nobau et al. (27). (B) Representative sleep profile and total sleep time of FoxP homozygous mutants (FoxP71.2, n = 14) compared with isogenic controls (n = 27). Homozygous FoxP mutants show severe locomotor impairments, with high immobility and lack of arousal at dusk/dawn, limiting unbiased sleep assessment. (C and G) Sleep profiles and their quantification. (D, E, H, and I) Average duration (D and H) and number of sleep bouts (E and I) in the light (LP, ZT0–12) and dark periods (DP, ZT12–24). FoxP71.2/5-SZ-3955 transheterozygous mutant males (n = 117) show reduced total sleep (P < 0.0001) (C) with shorter sleep bouts (P < 0.0001) (D), while the number of sleep bouts increased (P < 0.0001) (E) both during day and night compared with heterozygous Fox5-SZ-3955/+ flies (n = 116). (F and J) Latency to first sleep episode after lights-on and lights-off. (F) FoxP71.2/5-SZ-3955 mutants show longer latency to sleep onset after lights-on (P = 0.012) and shorter latency after lights-off (P < 0.0001). (G–J) Pan-neuronal FoxP-knockdown males (UAS-Dcr2,elav-Gal4 > UAS-FoxPRNAi-1, n = 66) show reduced sleep duration during both the day and night (P < 0.0001) compared with isogenic controls (UAS-Dcr2,elav-Gal4/+, n = 58). Moreover, they exhibit sleep fragmentation, with shorter but more frequent sleep bouts (P < 0.0001). SOL is unaffected. Flies were reared at 28°C. Data are presented as box-and-whisker plots showing the 25th to 75th percentiles, with the median indicated; whiskers represent the 5th and 95th percentiles. Statistical analysis was performed using 2-tailed unpaired t tests or Mann-Whitney tests, with Bonferroni correction for multiple comparisons. Significance: *P < 0.05 and ***P < 0.001.