Spargel/dPGC-1 is a new downstream effector in the insulin-TOR signaling pathway in Drosophila.
Insulin and target of rapamycin (TOR) signaling pathways converge to maintain growth so a proportionate body form is attained. Insufficiency in either insulin or TOR results in developmental growth defects due to low ATP level. Spargel is the Drosophila homolog of PGC-1, which is an omnipotent transcriptional coactivator in mammals. Like its mammalian counterpart, Spargel/dPGC-1 is recognized for its role in energy metabolism through mitochondrial biogenesis. An earlier study demonstrated that Spargel/dPGC-1 is involved in the insulin-TOR signaling, but a comprehensive analysis is needed to understand exactly which step of this pathway Spargel/PGC-1 is essential. Using genetic epistasis analysis, we demonstrated that a Spargel gain of function can overcome the TOR and S6K mediated cell size and cell growth defects in a cell autonomous manner. Moreover, the tissue-restricted phenotypes of TOR and S6k mutants are rescued by Spargel overexpression. We have further elucidated that Spargel gain of function sets back the mitochondrial numbers in growth-limited TOR mutant cell clones, which suggests a possible mechanism for Spargel action on cells and tissue to attain normal size. Finally, excess Spargel can ameliorate the negative effect of FoxO overexpression only to a limited extent, which suggests that Spargel does not share all of the FoxO functions and consequently cannot significantly rescue the FoxO phenotypes. Together, our observation established that Spargel/dPGC-1 is indeed a terminal effector in the insulin-TOR pathway operating below TOR, S6K, Tsc, and FoxO. This led us to conclude that Spargel should be incorporated as a new member of this growth-signaling pathway.
Department of Biology, Howard University, Washington, DC 20059.
Subhas
S
Mukherjee
Atanu
A
Duttaroy
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000254:growth & development; D004843:Epistasis, Genetic; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D007328:Insulin; C527201:pgc protein, Drosophila; D000255:Adenosine Triphosphate; C416303:target of rapamycin protein, Drosophila; D042925:Positive Transcriptional Elongation Factor B; D058570:TOR Serine-Threonine Kinases
Drosophila; PGC-1; Spargel; cell growth; insulin signaling