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

Autoři: Gianna W. Maurer aff001;  Alina Malita aff001;  Stanislav Nagy aff001;  Takashi Koyama aff001;  Thomas M. Werge aff002;  Kenneth A. Halberg aff001;  Michael J. Texada aff001;  Kim Rewitz aff001
Působiště autorů: Department of Biology, University of Copenhagen, Copenhagen, Denmark aff001;  Institute for Biological Psychiatry, Mental Health Centre Sct. Hans, Roskilde, Denmark aff002
Vyšlo v časopise: Analysis of genes within the schizophrenia-linked 22q11.2 deletion identifies interaction of night owl/LZTR1 and NF1 in GABAergic sleep control. PLoS Genet 16(4): e1008727. doi:10.1371/journal.pgen.1008727
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008727


The human 22q11.2 chromosomal deletion is one of the strongest identified genetic risk factors for schizophrenia. Although the deletion spans a number of known 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 night-time sleep in Drosophila. 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. Furthermore, nowl is required for metabolic homeostasis, suggesting that LZTR1 may contribute to the genetic susceptibility to obesity associated with the 22q11.2 DS. Knockdown of nowl or Nf1 in GABA-responsive sleep-promoting neurons elicits the sleep phenotype, and this defect can be rescued by increased GABAA receptor signaling, indicating that Nowl regulates sleep through modulation of GABA signaling. Our results suggest that nowl/LZTR1 may be a conserved regulator of GABA signaling important for normal sleep that contributes to the 22q11.2 DS.

Klíčová slova:

Drosophila melanogaster – Glycogens – Nervous system – Neurons – RNA interference – Sleep – Sleep disorders – Neurofibromatosis type 1


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