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 5

FoxP loss leads to circadian rhythmicity defects and abolishes PDF-secreting s-LNv neuron plasticity.

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FoxP loss leads to circadian rhythmicity defects and abolishes PDF-secre...
(A and B) Rhythmicity index (A) and proportion of rhythmic, weakly rhythmic, and arrhythmic flies (B) in FoxP71.2/5-SZ-3955 compound heterozygous mutant males (n = 28) compared with heterozygous hypomorphic Fox5-SZ-3955/+ flies (n = 25) and pan-neuronal FoxP-knockdown male flies (UAS-Dcr2,elav-Gal4 > UAS-FoxPRNAi-1, n = 69) compared with isogenic controls (UAS-Dcr2,elav-Gal4/+, n = 61). FoxP transheterozygous mutants and FoxP pan-neuronal knockdown leads to a lower rhythmicity index and increased arrhythmicity. (C) Schematic representation of the presynaptic terminals of s-LNv neurons in the morning (ZT2) and at night (ZT14). During early morning (ZT2), s-LNv projections are highly branched with high levels of PDF immunoreactivity, whereas during the night (ZT14), the projections are decreased and show lower PDF levels (80). (D and E) Example of synaptic terminal (D) and schematic illustration (E) of the image segmentation process employed for the quantitative analysis of s-LNv branching morphology. (F, I, and L) Representative images of PDF foci in s-LNv axonal terminals. Scale bar: 10 μm. (G, J, and M) Distribution of Cartesian (x, y) coordinates for each PDF-immunoreactive maximum. The distributions display the percentage of PDF-immunoreactive maxima along both the x and y dimensions. (H, K, and N) Percentage of PDF foci within area 2. (F–H) FoxP homozygous mutants (FoxP71.2, n = 30) compared with isogenic controls (n = 28) at ZT1–3 (morning). (I–K) FoxP homozygous mutants (FoxP71.2, n = 27) compared with isogenic controls (in gray, n = 25) at ZT13–15 (evening). (L–N) FoxP71.2/5-SZ-3955 compound heterozygous mutants (n = 27) compared with heterozygous hypomorphic Fox5-SZ-3955/+ flies (n = 25) at ZT1–3 (morning). 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 a 2-tailed unpaired t test. Significance: *P < 0.05 and ***P < 0.001.