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

Abstract

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 Rasdependent 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 GABA A 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.

Neurofibromin regulates metabolic rate via neuronal mechanisms in Drosophila

“…In mice, Nf1 heterozygosity reduces fat mass and alters various aspects of metabolism, such as glucose utilization, reminiscent of human NF1 12 . Nf1 knockdown also decreases glycogen in Drosophila 55 , along with the phenotypes reported here. Therefore, loss of Nf1 has the potential to regulate cellular and organismal metabolism, and these alterations in metabolism may contribute to the pathophysiology of NF1.…”

A unique Malpighian tubule architecture in Tribolium castaneum informs the evolutionary origins of systemic osmoregulation in beetles

“…To generate anti-Urn8R, anti-DH37 and anti-DH47 specific antibodies, we analyzed the amino acid sequence of the proteins to identify the most optimal immunizing peptide region according to a previously described method ( 59 ). These antibodies were subsequently used for immunocytochemistry ( 60 ) to visualize immunofluoresence in different tissues.…”

A nutrient-responsive hormonal circuit mediates an inter-tissue program regulating metabolic homeostasis in adult Drosophila

“…To analyze long-term locomotor activity of individual flies, we used the Drosophila activity monitor system (TriKinetics) in combination with the pySolo software package 74 and a custom MATLAB script (MATLAB R2016b, The MathWorks Inc, Natick, Massachusetts) as previously described 75 . Individual 4-day old flies of the appropriate genotype were housed in 65-mm-long glass tubes containing food (5% sucrose and 2% agar in water) in one end and a cotton plug in the other, which were assembled into the monitoring system.…”