Biology Reference
In-Depth Information
repression (
Vadla et al., 2012
). The mechanism for this is independent of the
let-7
family members, so something else must be repressing
hbl-1
. What this
repressor is and how the LIN-28 protein acts in this
let-7
-independent
mechanism remain unclear.
lin-28
also has a supportive role in
lin-14
expression, and visa versa.
Because
lin-4
targets each of these genes, when
lin-4
is removed both are
constitutively expressed (
Arasu, Wightman, & Ruvkun, 1991; Moss
et al., 1997
). Remove either one and the other is repressed (
Arasu et al.,
1991; Moss et al., 1997; Seggerson, Tang, & Moss, 2002
). Thus,
lin-14
and
lin-28
are tied to each other's expression, but again the molecular mech-
anisms are unknown. Nevertheless,
lin-28
is a stage-specific positive regu-
lator of three stage-specific effectors in the pathway:
lin-14
,
hbl-1
, and
lin-41
.
6. THE HETEROCHRONIC PATHWAY
There are three distinct phases of the heterochronic pathway, each
involving a microRNA switch and a connection to the next phase via a
key regulator (
Fig. 6.2
).
lin-4
and
lin-14
comprise the first phase, which tran-
sitions the animal from the L1 to the L2. As mentioned,
lin-4
is off early and
accumulates during the L1, but how its rise is controlled is not known.
lin-14
,
which appears to encode a transcription factor, seems to be all that is needed
to specify L1 fates. What was clear from an early analysis of a variety of
lin-14
mutant alleles is that
lin-14
also has a role in determining what happens in the
L2 (
Ambros &Horvitz, 1987
). It is believed that how it exerts that influence
is via its positive regulation of
lin-28
(
Pepper et al., 2004
). Thus,
lin-14
has a
direct role in specifying one stage, and influences a key regulator of the next.
The second phase is governed by
lin-28
and
hbl-1
, which are repressed by
lin-4
and the three
let-7
relatives, respectively.
hbl-1
seems to have the more
direct role in specifying L2 fates (
Abbott et al., 2005; Abrahante et al., 2003
).
But
lin-28
—like
lin-14
—has the interesting property of controlling two
consecutive stages: it positively regulates
hbl-1
and then positively regulates
lin-41
(by inhibiting
let-7
). The repression of
lin-41
by
let-7
, which leads ulti-
mately to the activation of
lin-29
, is the third phase. Recent data suggest the
let-7
/
lin-41
switch might directly regulate L3 fates (
Vadla et al., 2012
). It is
not yet clear if
lin-41
controls two larval stages; a great deal of investigation
needs to be done to fill in how this third phase works, including whether
lin-41
acts alone and how
lin-29
is repressed. It has been suggested that
lin-41
, whose mechanism is unclear, might act directly on
lin-29
post-
transcriptionally (
Del Rio-Albrechtsen, Kiontke, Chiou, & Fitch, 2006
).
