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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

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Maurer, Gianna W ; Malita, Alina ; Nagy, Stanislav ; Koyama, Takashi ; Werge, Thomas M ; Halberg, Kenneth A ; Texada, Michael J ; Rewitz, Kim. / Analysis of genes within the schizophrenia-linked 22q11.2 deletion identifies interaction of night owl/LZTR1 and NF1 in GABAergic sleep control. I: Plos Genetics. 2020 ; Bind 16, Nr. 4. s. e1008727.

Bibtex

@article{c81acc5a1c5b486d9b85ec6c0ff02b9a,
title = "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 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.",
keywords = "22q11 Deletion Syndrome/genetics, Adaptor Proteins, Signal Transducing/genetics, Animals, Drosophila, Drosophila Proteins/genetics, GABAergic Neurons/metabolism, Humans, Neurofibromin 1/genetics, Receptors, GABA-A/metabolism, Schizophrenia/genetics, Sleep/genetics, Transcription Factors/genetics",
author = "Maurer, {Gianna W} and Alina Malita and Stanislav Nagy and Takashi Koyama and Werge, {Thomas M} and Halberg, {Kenneth A} and Texada, {Michael J} and Kim Rewitz",
year = "2020",
month = apr,
day = "27",
doi = "10.1371/journal.pgen.1008727",
language = "English",
volume = "16",
pages = "e1008727",
journal = "Plos Genetics",
issn = "1553-7404",
publisher = "Public Library of Science",
number = "4",

}

RIS

TY - JOUR

T1 - Analysis of genes within the schizophrenia-linked 22q11.2 deletion identifies interaction of night owl/LZTR1 and NF1 in GABAergic sleep control

AU - Maurer, Gianna W

AU - Malita, Alina

AU - Nagy, Stanislav

AU - Koyama, Takashi

AU - Werge, Thomas M

AU - Halberg, Kenneth A

AU - Texada, Michael J

AU - Rewitz, Kim

PY - 2020/4/27

Y1 - 2020/4/27

N2 - 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.

AB - 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.

KW - 22q11 Deletion Syndrome/genetics

KW - Adaptor Proteins, Signal Transducing/genetics

KW - Animals

KW - Drosophila

KW - Drosophila Proteins/genetics

KW - GABAergic Neurons/metabolism

KW - Humans

KW - Neurofibromin 1/genetics

KW - Receptors, GABA-A/metabolism

KW - Schizophrenia/genetics

KW - Sleep/genetics

KW - Transcription Factors/genetics

UR - http://www.scopus.com/inward/record.url?scp=85084148777&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1008727

DO - 10.1371/journal.pgen.1008727

M3 - Journal article

C2 - 32339168

VL - 16

SP - e1008727

JO - Plos Genetics

JF - Plos Genetics

SN - 1553-7404

IS - 4

M1 - e1008727

ER -

ID: 61432682