Biology Reference
In-Depth Information
two miRNAs is partially redundant during eye development (
Hilgers
et al
., 2010
).
4.2. Epistasis analysis
Epistasis means “standing upon” and, in a genetic sense, refers to a situation
where the presence of one mutation masks the phenotype usually associated
with another mutation. An epistatic relationship associated with two oppo-
sitely directed mutants, as opposed to an intermediate phenotype of the
double mutant, can provide strong evidence that two genes act in a com-
mon pathway. Moreover, the direction of epistasis can inform which gene
acts upstream or downstream of the other. If mutant phenotypes are strictly
epistatic, then the double mutant will resemble the single mutant of the
downstream factor.
One of the most striking examples of miRNA epistasis involves bantam. As
mentioned, bantam is overtly essential for proliferation of imaginal disc tissues
as well as to suppress apoptosis of certain cell populations, and ectopic bantam
reciprocally drives strong disc overgrowths and prevents apoptosis. Both
activities are opposite to the functionof theHippo pathway, a highly conserved
signaling system that restricts tissue and organ size in flies and vertebrates (
Pan,
2010
). In brief, a major function of Hippo signaling is to repress the activity of
the Yorkie transcription cofactor. The first two transcriptional targets of
Yorkie elucidated were
diap1
and
cyclinE
, which makes sense given that the
former prevents cell death and the latter promotes cell cycle.
These opposite activities of Hippo signaling and bantam set the stage for
a relatively clean epistatic test: what is the phenotype of imaginal disc clones
that are doubly mutant for a Hippo pathway member (that gives disc
overgrowth) and bantam (which normally fail to grow)? The answer is
that bantam is epistatic, indicating that the disc overgrowths in Hippo
pathway mutant clones are driven by bantam function (
Nolo
et al
., 2006
;
Thompson and Cohen, 2006
). Reciprocally, constitutive activation of
Hippo signaling results in apoptosis and reduced proliferation. Strikingly,
this can be substantially rescued by forced activation of
bantam
, but not by
diap1
or
cyclinE
(
Nolo
et al
., 2006
;
Thompson and Cohen, 2006
).
Evidently, the combined activity of bantam as a progrowth, antiapopto-
tic factor defines it as a key downstream target for repression by hippo
signaling. Therefore, even though it is surely the case that Yorkie has many
targets genome-wide, the bantam miRNA must be one of its more impor-
tant effector molecules. A piece of the puzzle remains, however, since we
do not yet know of any relevant targets of bantam that can explain its pro-
proliferative capacity. Recall that suppression of apoptosis is not by itself
sufficient to explain tissue growth (
Brennecke
et al
., 2003
). Presumably,
epistatic analysis with the appropriate growth-suppressing molecules may
shed light on this issue.
