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 4

FoxP is required during development for adult sleep.

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FoxP is required during development for adult sleep. (A) Schematic repre...
(A) Schematic representation of the TARGET system. (B) Temperature shifts used to induce posteclosion FoxP knockdown, restricting it to adulthood. (C–E) Representative data for total sleep time (C), average sleep bout duration (D), and number of sleep bouts (E) during the light period (LP, ZT0–12) and dark period (DP, ZT12–24) in flies with pan-neuronal FoxP knockdown exclusively during posteclosion stages (tub-Gal80ts, elav-Gal4; UAS-Dcr2 > UAS-FoxPRNAi-1, n = 16) compared with isogenic controls (tub-Gal80ts, elav-Gal4; UAS-Dcr2/+, n = 16). Posteclosion FoxP knockdown does not affect sleep. (F) Temperature shifts used to induce FoxP knockdown throughout developmental stages prior to eclosion only. (G–I) Representative data for total sleep time (G), average sleep bout duration (H), and number of sleep bouts (I) during the light period (ZT0–12) and dark period (ZT12–24) in flies with pan-neuronal FoxP knockdown during pre-eclosion stages (tub-Gal80ts, elav-Gal4; UAS-Dcr2 > UAS-FoxPRNAi-1, n = 26) compared with isogenic controls (tub-Gal80ts, elav-Gal4; UAS-Dcr2/+, n = 29). FoxP knockdown during developmental stages prior to eclosion is necessary and sufficient to cause decreased and fragmented sleep. 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, **P < 0.01, and ***P < 0.001.