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Fig. 6. A model for regulation of C. elegans larval development,
metabolism and longevity. Proposed wild-type functions are shown, with arrows
indicating stimulation of activities and T-bars indicating inhibition, but the
steps do not indicate direct protein interactions. Bold arrows represent
changes in wild-type activities. Both daf-15 and daf-2
pathways are essential for larval development. Null mutations result in larval
lethality. (A) When food is abundant, LET-363/DAF-15 transduces a sufficient
nutrient signal to permit growth to the reproductive adult. This signal is
also required for DAF-2/insulin signaling to stimulate growth. Disruption of
either pathway will cause larval arrest at the second molt. Food availability
could also regulate the DAF-2/insulin pathway. (B) When nutrients are limited,
the LET-363/DAF-15 signal is insufficient to prevent larval arrest. With
concomitant down regulation of the DAF-2 pathway, animals will enter the dauer
stage. When DAF-16 activity is high, TOR activity is low, and vice versa.
However, in a daf-15 or let-363 mutant TOR activity is low
even when insulin/IGF signaling is high, resulting in activation of some
target functions, such as autophagy, but the reduced activity of DAF-16 fails
to activate other functions needed to complete dauer morphogenesis.
daf-15 is epistatic to daf-2 because some targets of TOR
that are essential for dauer morphogenesis fail to be activated in the absence
of DAF-15 function. Essentially, knockout of LET-363/DAF-15 activity results
in dauer-like arrest regardless of DAF-2 signaling because LET-363/DAF-15 is
required for both dauer and non-dauer development. TOR regulates autophagy,
which is required for dauer morphogenesis and for the increased longevity of
daf-2 adults, but TOR activity is also required for maturation to the
adult. DAF-16 and LET-363/DAF-15 have other downstream targets not shown
here.
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