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

by Gianna W. Maurer, Alina Malita, Stanislav Nagy, Takashi Koyama, Thomas M. Werge, Kenneth A. Halberg, Michael J. Texada, Kim Rewitz 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 geneLZTR1 (night owl,nowl) as a regulator of night-time sleep inDrosophila. In humans,LZTR1 has been associated with Ras-dependent neurological diseases also caused byNeurofibromin-1 (Nf1) deficiency. We show thatNf1 loss leads to a night-time sleep phenotype nearly identical to that ofnowl loss and thatnowl negatively regulates Ras and interacts withNf1 in sleep regulation. Furthermore,nowl is required for metabolic homeostasis, suggesting thatLZTR1 may contribute to the genetic susceptibility to obesity associated with the 22q11.2 DS. Knockdown ofnowl orNf1 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 thatnowl/LZTR1 may be a conserved regulator of GABA ...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research