Biology Reference
In-Depth Information
reverse the process and restart reproductive development from the point
where it left off.
DAF-12 is distinctive among worm nuclear receptors in that its ligands,
the dafachronics acids (DA) have been identified (
Held et al., 2006; Motola
et al., 2006
) (see also
Chapter 7
). These cholesterol-derived steroidal ligands
bind to DAF-12 during favorable growth conditions and promote repro-
ductive development. In adverse conditions of elevated temperature and/
or limited food supply, DA levels are low and ligand-free DAF-12 binds
the DIN-1 corepressor and promotes dauer formation (
Ludewig et al.,
2004
). Consequently, DAF-12 acts as a switch to modulate nematode life
history. Animals lacking
daf-12
activity altogether are dauer defective and
undergo reproductive development regardless of conditions. Developmen-
tal timing programs in these animals are largely normal, with only a weakly
penetrant reiteration of L2 programs at the L3 stage. However, this retarded
phenotype predominates in mutants where DAF-12 is truncated in the
ligand binding domain, and it is likely to arise from ligand-free DAF-12
acting with DIN-1 as a constitutive repressor (
Antebi et al., 1998, 2000
).
DAF-12 is thus absolutely required for dauer formation at the L2 molt,
but plays a more modulatory role in the heterochronic pathway by helping
to control the L2 to L3 transition.
LIN-42 inhibits dauer formation by antagonizing ligand-free DAF-12,
thereby promoting continuous development under conditions of mild stress
and adding a level of robustness to the dauer decision (
Tennessen et al.,
2010
). At elevated temperatures,
lin-42
mutants constitutively enter the
dauer pathway in a DIN-1-dependent manner. Consistent with a role in
preventing dauer formation, LIN-42 levels are dramatically reduced in lar-
vae destined to be dauers, and forced expression of LIN-42 in this stage can
bypass dauer formation.
lin-42
and
daf-12
also act in opposition during con-
tinuous development;
lin-42
;
daf-12
double mutants exhibit mutual suppres-
sion of epidermal phenotypes (
Tennessen et al., 2006
). Together, these
genes indirectly sense external stimuli and make the choice between repro-
duction and an extended juvenile phase.
The mechanism by which DAF-12 coordinates postembryonic develop-
mental progression is coming into focus through the identification of its
direct targets. DAF-12 targets appear diverse, as might be expected given
its global roles in development and aging, but conspicuously include core
heterochronic pathway components, such as
hbl-1
,
lin-28
,
lin-41
, and
lin-42
, as well as the
din-1
,
daf-12
's partner in dauer formation
(
Hochbaum et al., 2011
). Directed studies are now required to tease apart
