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In-Depth Information
be expressed throughout larval development resulting in reiteration of
L1-specific events. The transition from L1- to L2-specific events is governed
by this microRNA switch.
In addition to
lin-4
, several other microRNA genes act in the pathway:
let-7
and its three relatives
mir-48
,
mir-84
, and
mir-241
(
Abbott et al., 2005;
Reinhart et al., 2000
). The
let-7
family of microRNAs share nearly identical
5
0
halves of their short 22-nucleotide lengths. Theory predicts that these
microRNAs can target the same mRNAs, although whether or not they
do
in vivo
is an open question. The three
let-7
relatives are expressed with
nearly identical profiles and act redundantly to repress
hbl-1
, which encodes
a Hunchback-like transcription factor that controls the transition from L2 to
L3 (
Abbott et al., 2005; Abrahante et al., 2003; Lin et al., 2003
).
let-7
accu-
mulates slightly later and its primary target is
lin-41
, which appears to encode
an RNA-regulatory protein or ubiquitin ligase (
Loedige, Gaidatzis, Sack,
Meister, & Filipowicz, 2012; Reinhart et al., 2000; Slack et al., 2000
). There
is some controversy about whether it controls the L3 to L4 transition or the
L4 to adult transition (
Vadla, Kemper, Alaimo, Heine, & Moss, 2012
).
In general, the microRNAs show an expression profile that is “off early,
on late,” and their targets are “on early, off late” (
Fig. 6.2
, bottom). What
distinguishes these switches is the time of accumulation of the microRNA
and the consequent time of repression of the target. Although largely still ill-
defined, some mechanisms controlling microRNA accumulation have been
found.
5. LIN-28: A microRNA REGULATOR AT THE PATHWAY
'
S
CENTER
A second target of the
lin-4
microRNA is
lin-28
(
Moss, Lee, &Ambros,
1997
).
lin-28
encodes a small RNA-binding protein that is known to bind the
precursor of the
let-7
microRNA and block its maturation, thereby
supporting
lin-41
against repression (
Lehrbach et al., 2009; Moss et al.,
1997; Vadla et al., 2012; Van Wynsberghe et al., 2011; Viswanathan,
Daley, & Gregory, 2008
). It does this by recruiting a poly(U) polymerase
(encoded by
pup-2
) that helps to stimulate the degradation of the
let-7
pre-
cursor RNA (
Heo et al., 2008
). Thus, the accumulation of
let-7
is prevented
until
lin-28
is repressed by
lin-4
.
However, repressing
let-7
is not all that
lin-28
does. As mentioned above,
lin-28
's primary role is to promote L2 events. Neither
let-7
nor
lin-41
con-
trols the L2. Instead,
lin-28
appears to act via
hbl-1
, supporting
hbl-1
against
