Biology Reference
In-Depth Information
Collectively these data suggest a model whereby germline removal stim-
ulates DA/DAF-12 signaling and expression of the
let
-
7
microRNAs
(
Fig. 7.4
). These in turn diminish expression of AKT-1 and LIN-14, and
thereby activate DAF-16/FOXO. Together DAF-16 and DAF-12, as well
as other transcriptional regulators, promote longevity genes. What is
remarkable about these findings is that multiple components of the gonadal
longevity network DA,
daf
-
12
,
mir
-
84
,
mir
-
241
, and
lin
-
14
are also key
players in the heterochronic circuitry, revealing an intimate connection
between developmental timing and life span regulation. Notably, in the
heterochronic circuit, DAF-12 turns on these microRNAs, which then turn
off earlier L2 programs to make way for L3 programs. Conceivably in the
context of the gonadal pathway, DAF-12 turns on these microRNAs to
switch between a reproductive mode and a survival mode of adulthood
in response to environmental and physiologic conditions (
Fig. 7.4
).
Two important questions come to mind. What is the ecological signif-
icance of germline loss and why could the heterochronic genes be involved?
It is quite possible that under environmental stress, nutrient limitation,
or infection, the germline arrests proliferation. For example, it is known that
in worms that are nutrient limited, the germline and gonad retract and go
into a state of quiescence (
Angelo & Van Gilst, 2009
). Heterochronic activ-
ities may be invoked as a mechanism to coordinate the relative timing of
events between gonad and soma, so that they mature concurrently. From
an evolutionary perspective, this would be critical to future reproductive
success, but with secondary consequences for the life span.
Taken together the finding that first
daf
-
12
steroidal signaling (
Gerisch
et al., 2001; Hsin & Kenyon, 1999
), then
lin
-
14
,
lin
-
4
, and the
let
-
7
micro-
RNAs all affect life span (
Boehm & Slack, 2005; Shen et al., 2012
) reveals an
important connection between developmental timing components, matura-
tion, and longevity. In mammals, the
let
-
7
microRNAs have been impli-
cated in regulating insulin signaling and glucose homeostasis (
Zhu et al.,
2011
), raising the possibility that such microRNAs could also affect longev-
ity circuits in higher animals.
5. PERSPECTIVES
Pioneering studies in
C
.
elegans
reveal that environmental cues are
integrated by major growth factor pathways, including IIS and TGF-
b
sig-
naling, which converge on steroidal receptor DAF-12. Depending on DA
availability DAF-12 either triggers reproductive maturation by activating
