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Analysis of genes within the schizophrenia-linked 22q11.2 deletion identifies interaction of night owl/LZTR1 and NF1 in GABAergic sleep control

By Gianna W. Maurer, Alina Malita, Stanislav Nagy, Takashi Koyama, Thomas Werge, Kenneth A. Halberg, Michael J. Texada, Kim Rewitz

Posted 05 Sep 2019
bioRxiv DOI: 10.1101/755454

The human 22q11.2 chromosomal deletion is one of the strongest identified genetic risk factors for schizophrenia. Although the deletion spans a number of genes, the contribution of each of these to the 22q11.2 deletion syndrome (DS) is not known. To investigate the effect of individual genes within this interval on the pathophysiology associated with the deletion, we analyzed their role in sleep, a behavior affected in virtually all psychiatric disorders, including the 22q11.2 DS. We identified the gene LZTR1 ( night owl, nowl ) as a regulator of sleep in Drosophila . Neuronal loss of nowl causes short and fragmented sleep, especially during the night. In humans, LZTR1 has been associated with Ras-dependent neurological diseases also caused by Neurofibromin-1 ( Nf1 ) deficiency. We show that Nf1 loss leads to a night-time sleep phenotype nearly identical to that of nowl loss, and that nowl negatively regulates Ras and interacts with Nf1 in sleep regulation. We also show that nowl is required for metabolic homeostasis, suggesting that LZTR1 may contribute to the genetic susceptibility to obesity associated with the 22q11.2 DS. Furthermore, knockdown of nowl or Nf1 in GABA-responsive sleep-promoting neurons elicits the sleep-fragmentation phenotype, and this defect can be rescued by increased GABAA receptor signaling, indicating that Nowl promotes sleep by decreasing the excitability of GABA-responsive wake-driving neurons. Our results suggest that nowl / LZTR1 may be a conserved regulator of GABA signaling and sleep that contributes to the 22q11.2 DS.

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