Sleep is induced by sleep-active neurons that are conserved from mammals to C. elegans. These neurons express GABA and neuropeptides, are active at the onset of sleep and actively promote it. However, little is known about how sleep neuron cell fate is determined and how sleep neurons induce this behavior.
In C. elegans, sleep-like behavior occurs during lethargus, preceding the molt (Cassada and Russell 1975, Raizen et al. 2008). It depends on the sleep-active sleep-promoting neuron RIS, which requires the AP2 transcription factor APTF-1 to induce sleep (Turek et al. 2013). Thus, APTF-1 provides a unique starting point to understand sleep neuron specification and sleep induction.
We combined transcriptome analysis of aptf-1 mutants with analysis of RIS-expressed genes to find out what determines expression of APTF-1 and how APTF-1 causes RIS to become sleep promoting. We found that the lim box homeodomain transcription factor LIM-6, which broadly specifies GABAergic neuron fate (Hobert et al. 1999), determined the expression of APTF-1 in RIS. Transcriptome analysis of aptf-1 mutants showed that APTF-1 is required for the expression of an FMRFamide-like neuropeptide, FLP-11, in RIS. Deletion of FLP-11 caused substantially reduced sleep behavior during lethargus, an effect that was increased by knockout of GABA. Overexpression of FLP-11 caused ectopic sleep behavior, confirming that this peptide is somnogenic. FLP-11 has been shown to activate three receptors, NPR-22, NPR-4, and FRPR-3 (Peyman et al. 2014). All these receptors appeared to contribute to the induction of sleep behavior downstream of FLP-11 release by RIS.
Thus, we present a mechanism of how RIS becomes sleep inducing: LIM-6 causes APTF-1 expression, which in turn causes expression of the somnogenic peptide FLP-11. At the onset of sleep, RIS is strongly activated and releases both GABA and FLP-11, which activates multiple receptors to globally induce sleep. Like mammalian sleep-active neurons, RIS uses both peptidergic and GABAergic signaling to induce sleep, which further supports the view of a common evolutionary origin of sleep neurons.
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