Cell-nonautonomous signaling of FOXO/DAF-16 to the stem cells of Caenorhabditis elegans
16.08.2012
Qi W, Huang X, Neumann-Haefelin E, Schulze E, Baumeister R.
PLoS Genet. 2012;8(8):e1002836
Transgenic daf 16 causes multiple developmental defects which are strongly enhanced in shc 1 mutants. The most prominent phenotype is a tumorous proliferation of the germ line and disruption of the surrounding extracellular matrix, which kills the animals. Inhibition of germline mitosis by an anti-cancer chemotherapeutic drug FUdR, or by inactivation of the Notch signalling pathway, accordingly, extends lifespan of these animals.
Expression analysis demonstrated that DAF 16 sends a signal from the epidermis to the reproductive system to cause the germline phenotypes. In contrast, a SHC 1, MEK-1 and KGB-1 mediated JNK signalling in the musculature antagonizes this DAF 16 activity.
Inactivation of IIR signalling inhibits germline proliferation and therefore, prevents the gonadal disruption. Activation of IIR signalling in PTEN daf 18 mutants enhances the gonad disruption phenotype of daf 16 transgenic animals. All these data indicate that an active IIR signalling is required for DAF 16 to cause the tumorous germline development. In contrast to IIR signalling, AKT-1 inhibits DAF-16 activity causing disruption of the gonad.
Despite of the numerous studies supporting a pro-longevity role of DAF 16, in the previous studies transgenic daf 16 failed to extend lifespan. A possible inactivation of the daf 16 transgene by AKT 1/2 has been proposed to be the cause for that. This work indicates that transgenic DAF 16 can extend lifespan, when its negative impact on the germ line is inhibited. It illustrates that DAF-16 expression may have two consequences dependent on its activation profile: It can extend or shorten lifespan. The genetic context controls both aspects allowing the future search for novel factors regulating DAF 16 expression and activity.
