Biology Reference
In-Depth Information
While activating
let-7-C
miRNAs on the one hand, Ecdysone signaling
also represses
miR-8
,
miR-14
, and
miR-34
on the other. Repression of
miR-8
and
miR-14
occurs at the transcriptional level, since Ecdysone treatment of
cultured cells and tissues leads to a decrease in the levels of
pri-miR-8
as well
as
pri-miR-14
(
Jin et al., 2012; Varghese & Cohen, 2007
). Endogenous EcR
activity is required for this repression and, at least in the case of
miR-8
, acts
through its direct transcriptional targets,
Eip74ef
and
br
.A
miR-8
enhancer
fragment containing multiple predicted
Eip74ef
and
br
binding sites mediates
repression of a reporter gene, and mutational analysis indicates that two of
these
Eip74ef
binding sites are at least partially responsible (
Jin et al., 2012
).
miR-8
and
miR-14
regulate components of the IIS pathway, offering a direct
molecular connection between the Ecdysone and IIS pathways as discussed
further below. In addition,
miR-14
feeds back to directly repress the expres-
sion of EcR. The EcR/
miR-14
circuit provides a mechanism for amplifying
EcR expression in response to Ecdysone. The molecular basis for Ecdysone
regulation of
miR-34
is less clear. The locus encoding
miR-34
is likely to be
complex, since profiling arrays indicate that
miR-34
is co-transcribed with
two other miRNAs,
miR-277
and
miR-317
(
Kadener, Rodriguez, et al.,
2009
). Determining whether Ecdysone affects
miR-277
and
miR-317
levels
should shed light on whether the hormonal regulation of
miR-34
occurs at
the transcriptional or post-transcriptional levels.
4.4. Biological roles of Ecdysone regulated let-7-C miRNAs
Steroid hormone induction of
let-7
family miRNAs appears to be conserved
feature of animal development, since it is shared by both flies and nematodes
(for additional review, see
Sokol, 2012
).
C. elegans
stage-specific miRNAs
are activated by the dafachronic acid steroid hormone to ensure that cells
within lineages throughout the animal adopt stage specific cell fates
(
Bethke, Fielenbach, Wang, Mangelsdorf, & Antebi, 2009
). Disruption of
this pathway leads to clear temporal cell fate transformations that are appar-
ent through the transparent cuticle of the adult. In miRNA mutants, for
example, cells inappropriately reiterate mitotic programs of previous devel-
opmental stages and this frequently leads to inappropriate proliferation of
cells that were scheduled to terminally differentiate. Genetic elimination
of
Drosophila let-7-C
miRNAs has little effect on the morphology and timing
of development at the organismal level:
let-7-C
mutant animals proceed
through development on schedule and eclose with wildtype appearance
(
Caygill & Johnston, 2008; Sokol et al., 2008
). But newly eclosed
let-7-C
