Abstract
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.
Highlights
Normal tissue functions, including growth, maintenance, and regeneration, depend on the availability of energy provided by food or reservoirs like glycogen and lipids
Because we wanted to determine whether we could use fruit flies to investigate the role of SHP2 in metabolism and life span, we began by examining the effect of reducing CSW in fruit flies on life span
To understand the role of SHP2 in survival, we investigated the effect of suppressing CSW function, the orthologous phosphatase in Drosophila
Summary
Normal tissue functions, including growth, maintenance, and regeneration, depend on the availability of energy provided by food or reservoirs like glycogen and lipids. Growth depends on growth hormone and, in turn, insulin-like growth factors (e.g., IGF1), which promote the activation of the RAS-ERK1/2 signaling pathway. In Drosophila, both functions are mediated by the insulin and insulin-like growth factor signaling (IIS) pathway downstream of a single insulin receptor (InR) (Reyes-DelaTorre et al, 2012; Rajan and Perrimon, 2013). A large number of studies have shown evolutionarily conserved functional signaling mechanisms between fruit flies and vertebrates, like the insulin/IGF/target of rapamycin pathway (Oldham and Hafen, 2003; Reyes-DelaTorre et al, 2012). Accumulating evidence shows that insulin signaling affects metabolism in vertebrates and invertebrates with profound effects on survival (Kenyon et al, 1993; Böhni et al, 1999; Clancy et al, 2001; Tatar et al, 2001; Blüher et al, 2003)
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