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is important to establish and reinforce robust developmental decisions
(
Hochbaum et al., 2011
). Although expression of these genes in human cell
culture shows clear DA and DAF-12 dependence, the requirement
in vivo
is
more modest or even absent. Conceivably other transcription factors can
come in to do the job, highlighting functional redundancy, or DAF-12 reg-
ulation might operate only under specific conditions, such as dauer entry
or exit.
3.5. daf-12 is feedback regulated by the let-7 microRNAs
Transcriptional feedback loops play an important role in timing devices as
well as homeostatic regulation. Interestingly, the
daf
-
12
3
0
untranslated
region (UTR) contains multiple
let
-
7
-binding sites, which mediate feedback
regulation by
let
-
7
family microRNAs. In wild type, DAF-12 protein peaks
around early L3 and then diminishes into L4. By contrast, in the
mir
-
48
,
mir
-
84, mir
-
241
triple mutant, DAF-12 expression, as measured with full-length
daf
-
12
::
gfp
or 3
0
UTR reporter constructs, is sustained to later stages
(
Hammell, Karp, & Ambros, 2009
). Moreover, microRNA deletion results
in increased DAF-12 repressor activity under limiting hormone conditions,
exacerbating gonadal cell migration defects, and biasing dauer formation.
Such feedback regulation might be important for temporal control of
DAF-12 activity as well as modulating activity in the face of fluctuating
environments.
Similarly,
let
-
7
regulates DAF-12 levels through its 3
0
UTR during the L4/
adult transition (
Grosshans, Johnson, Reinert, Gerstein, & Slack, 2005
).
let
-
7
mediates terminal differentiation events at the L4/adult switch and loss-of-
function mutations result in retarded phenotypes in which seam cells fail to
express adult fates on schedule (
Reinhart et al., 2000
). Consistent with a
downstream functional role,
daf
-
12
mutation suppresses
let
-
7
phenotypes.
Moreover,
daf
-
12
mutants on their own exhibit mild precocious seam cell
fusion phenotypes, and enhance the precocious phenotypes of
lin
-
41
/Trim71
mutants. These observations are somewhat puzzling since they suggest that
daf
-
12
(
) retards development at the L4/adult switch, but advances develop-
ment at the L2/L3 transition. Speculatively, this janus-like behavior in both
retarding and advancing development could reflect its switch like capabilities.
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3.6. daf-12 acts in opposition to lin-42/period
One of the key global regulators of
C
.
elegans
life history is
lin
-
42
, a homolog
of the circadian oscillator regulator
period
(
Jeon, Gardner, Miller, Deshler, &