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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, &
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