Abstract
Across species, sleep in young animals is critical for normal brain maturation. The molecular determinants of early life sleep remain unknown. Through an RNAi-based screen, we identified a gene, pdm3, required for sleep maturation in Drosophila. Pdm3, a transcription factor, coordinates an early developmental program that prepares the brain to later execute high levels of juvenile adult sleep. PDM3 controls the wiring of wake-promoting dopaminergic (DA) neurites to a sleep-promoting region, and loss of PDM3 prematurely increases DA inhibition of the sleep center, abolishing the juvenile sleep state. RNA-Seq/ChIP-Seq and a subsequent modifier screen reveal that pdm3 represses expression of the synaptogenesis gene Msp300 to establish the appropriate window for DA innervation. These studies define the molecular cues governing sleep behavioral and circuit development, and suggest sleep disorders may be of neurodevelopmental origin.
Highlights
Across species, sleep amounts are highest in early life and decrease as animals mature (Kayser and Biron, 2016; Roffwarg et al, 1966)
Pdm3 is part of the POU domain transcription factor family, a gene group with essential roles in nervous system patterning across species (Badea et al, 2012; Dominguez et al, 2013; Olsson-Carter and Slack, 2011)
We have identified the transcription factor, pdm3, as a genetic regulator of sleep ontogeny
Summary
Sleep amounts are highest in early life and decrease as animals mature (Kayser and Biron, 2016; Roffwarg et al, 1966). The fruit fly, Drosophila melanogaster, exhibits increased sleep duration in young adulthood that tapers with maturity (Dilley et al, 2018; Kayser et al, 2014; Shaw et al, 2000). Genes regulating sleep ontogenetic change are likely distinct from those that control sleep duration. Young versus mature sleep amounts in primary and secondary sleep ontogeny screens. Blocking DA signaling to the dFSB rescues sleep ontogeny in flies lacking PDM3, demonstrating that greater inhibitory DA signaling to the sleep center prevents young flies from achieving high sleep amounts. Transcriptional profiling of mid-pupal brains and a subsequent genetic modifier screen reveal that pdm regulates expression of the synapse assembly gene, Msp300, to control sleep ontogeny. Miswiring during early development leads to a brain structural abnormality that disrupts the normal ontogeny of sleep behavior
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