A Drosophila Genome-Wide Screen Identifies Regulators of Steroid Hormone Production and Developmental Timing.
Steroid hormones control important developmental processes and are linked to many diseases. To systematically identify genes and pathways required for steroid production, we performed a Drosophila genome-wide in vivo RNAi screen and identified 1,906 genes with potential roles in steroidogenesis and developmental timing. Here, we use our screen as a resource to identify mechanisms regulating intracellular levels of cholesterol, a substrate for steroidogenesis. We identify a conserved fatty acid elongase that underlies a mechanism that adjusts cholesterol trafficking and steroidogenesis with nutrition and developmental programs. In addition, we demonstrate the existence of an autophagosomal cholesterol mobilization mechanism and show that activation of this system rescues Niemann-Pick type C1 deficiency that causes a disorder characterized by cholesterol accumulation. These cholesterol-trafficking mechanisms are regulated by TOR and feedback signaling that couples steroidogenesis with growth and ensures proper maturation timing. These results reveal genes regulating steroidogenesis during development that likely modulate disease mechanisms.
Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark.
E Thomas
ET
Danielsen
Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark.
Morten E
ME
Moeller
Department of Entomology, University of California, Riverside, Riverside, CA 92521, USA; Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA.
Naoki
N
Yamanaka
Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada.
Qiuxiang
Q
Ou
Center for Biological Sequence Analysis, DTU Systems Biology, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark.
Janne M
JM
Laursen
Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark.
Caecilie
C
Soenderholm
Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada.
Ran
R
Zhuo
Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada.
Brian
B
Phelps
Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada.
Kevin
K
Tang
Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada.
Jie
J
Zeng
Genetic Strains Research Center, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan.
Shu
S
Kondo
Department of Biochemistry and Molecular Biology, Villum Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark.
Christian H
CH
Nielsen
Department of Biochemistry and Molecular Biology, Villum Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark.
Eva B
EB
Harvald
Department of Biochemistry and Molecular Biology, Villum Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark.
Nils J
NJ
Faergeman
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA.
Macy J
MJ
Haley
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA.
Kyle A
KA
O'Connor
Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada.
Kirst
K
King-Jones
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA.
Michael B
MB
O'Connor
Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark. Electronic address: kim.rewitz@bio.ku.dk.
Kim F
KF
Rewitz
D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000235:genetics; D001692:Biological Transport / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics*; D004440:Ecdysone / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics*; D000081031:Fatty Acid Elongases; D005820:Genetic Testing; D049750:Genome, Insect; D006728:Hormones / Q000096:biosynthesis*; D050356:Lipid Metabolism / Q000235:genetics; D010641:Phenotype; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics; D013107:Sphingolipids / Q000378:metabolism; D013256:Steroids / Q000096:biosynthesis*; D013997:Time Factors
D029721:Drosophila Proteins; D006728:Hormones; D013107:Sphingolipids; D013256:Steroids; D004440:Ecdysone; D002784:Cholesterol; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases