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fusions; the promoter remains inactive unless food is present (
Baugh &
Sternberg, 2006
). Important for understanding how temporal development
initiates then is to link nutritional cue(s) supplied by
E. coli
to signaling
pathways in the worm that ultimately activate
lin-4
setting off the pathway.
Some clues to the mechanism of L1 arrest are beginning to emerge. Notably,
components of the insulin/IGF signaling pathway are required for the main-
tenance of L1 diapause (
Baugh & Sternberg, 2006; Fukuyama, Rougvie, &
Rothman, 2006; Gems et al., 1998
). Animals mutant for DAF-18/PTEN or
DAF-16/FOXO initiate postembryonic programs involving cell division,
migration, and cell fusion events even under starvation conditions and have
reduced survival rates during L1 diapause.
miRNAs help couple nutrient availability to the activation of larval pro-
grams. miRNAs have been identified that are required for the maintenance
of L1 diapause, survival during diapause, or whose levels correlate with L1 dia-
pause entry and/or exit (
Karp, Hammell, Ow, & Ambros, 2011; Kasuga,
Fukuyama, Kitazawa, Kontani, & Katada, 2013; Zhang, Zabinsky, Teng,
Cui, & Han, 2011
). Perhaps most intriguing among these are miR-235 and
miR-71. Similar to insulin pathway mutants, miR-235 is required for the
arrest of developmental programs during L1 diapause; in its absence, the acti-
vation of
lin-4
and
lin-42
is observed, blast cells divide and molting cycles ini-
tiate, even when food is lacking (
Kasuga et al., 2013
). Although much remains
to be learned about how activity of this miRNA feeds into heterochronic gene
regulation, an insulin pathway mediated reduction in miR-235 levels appears
to be an important step in launching larval development.
mir-71
links L1 diapause with postembryonic developmental timing in a
surprisingly different way. The loss of
mir-71
has little phenotypic conse-
quence during continuous larval development (
Miska et al., 2007
) but, unex-
pectedly,
mir-71
mutants develop with retarded heterochronic defects in the
vulva if they have experienced L1 diapause (
Zhang et al., 2011
). This result
suggests that
mir-71
plays a role in ensuring developmental robustness when
the worm enters L1 arrest. Further, it predicts that
mir-71
targets mRNAs of
proteins whose over-expression would delay the resumption of vulval pro-
grams upon feeding; that is, perhaps
mir-71
interfaces with heterochronic
gene regulation. Indeed, miR-71 binding sites are predicted in the 3
0
UTRs
of two temporal regulators of vulva development,
lin-42
and
hbl-1
, and these
UTRs are
mir-71
-repsonsive during L1 diapause. Given that the loss of
lin-42
or
hbl-1
activity causes precocious defects in vulva formation during contin-
uous development (
Abrahante et al., 2003; Tennessen et al., 2006
), their
