The Phosphatase CSW Controls Life Span by Insulin Signaling and Metabolism Throughout Adult Life in Drosophila

被引:7
作者
Ruzzi, Leonardo R. [1 ]
Schilman, Pablo E. [2 ]
San Martin, Alvaro [1 ]
Lew, Sergio E. [3 ]
Gelb, Bruce D. [4 ,5 ,6 ]
Pagani, Mario R. [1 ]
机构
[1] Univ Buenos Aires, Dept Physiol & Biophys, Natl Sci & Tech Res Council, Sch Med, Buenos Aires, DF, Argentina
[2] Univ Buenos Aires, Fac Exact & Nat Sci, Natl Sci & Tech Res Council, Dept Biodivers & Expt Biol, Buenos Aires, DF, Argentina
[3] Univ Buenos Aires, Inst Biomed Engn, Fac Engn, Buenos Aires, DF, Argentina
[4] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA
[5] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA
[6] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA
基金
美国国家卫生研究院;
关键词
CSW loss and gain-of-function mutations; life span; Drosophila; insulin signaling; metabolism; DIETARY-RESTRICTION; GENE-EXPRESSION; NOONAN-SYNDROME; STEM-CELLS; PTPN11; SHP2; RECEPTOR; HOMEOSTASIS; MUTATIONS; MICE;
D O I
10.3389/fgene.2020.00364
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Noonan syndrome and related disorders are caused by mutations in genes encoding for proteins of the RAS-ERK1/2 signaling pathway, which affect development by enhanced ERK1/2 activity. However, the mutations' effects throughout adult life are unclear. In this study, we identify that the protein most commonly affected in Noonan syndrome, the phosphatase SHP2, known in Drosophila as corkscrew (CSW), controls life span, triglyceride levels, and metabolism without affecting ERK signaling pathway. We found that CSW loss-of-function mutations extended life span by interacting with components of the insulin signaling pathway and impairing AKT activity in adult flies. By expressing csw-RNAi in different organs, we determined that CSW extended life span by acting in organs that regulate energy availability, including gut, fat body and neurons. In contrast to that in control animals, loss of CSW leads to reduced homeostasis in metabolic rate during activity. Clinically relevant gain-of-function csw allele reduced life span, when expressed in fat body, but not in other tissues. However, overexpression of a wild-type allele did not affect life span, showing a specific effect of the gain-of-function allele independently of a gene dosage effect. We concluded that CSW normally regulates life span and that mutations in SHP2 are expected to have critical effects throughout life by insulin-dependent mechanisms in addition to the well-known RAS-ERK1/2-dependent developmental alterations.
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页数:15
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