Biology Reference
In-Depth Information
2000
). In
C. elegans
loss of
lin-41
, a direct let-7 target, results in premature
cellular differentiation (
Fig. 1.3
;
Reinhart
et al.
, 2000; Slack
et al.
,2000
).
Consistent with its role in promoting the undifferentiated state in worms,
the mouse homolog is concentrated in stem and early embryonic cells (
Rybak
et al.
, 2009
). Although themolecular function of the
C. elegans
LIN-41 protein
is not yet known, recent work in mouse cells shows that mLin41 acts as an E3
ubiquitin ligase that modifies Ago2, reducing its stability (
Rybak
et al.
, 2009
).
Thus, mLin41 can indirectly regulate the levels and function of mature
miRNAs by antagonizing Argonaute (
Fig. 1.7
).
As mentioned above, several targets of let-7 are transcription factors.
Loss of
hbl-1
or
daf-12
activity results in precious expression of adult fates in
larval stage worms (
Abrahante
et al.
, 2003; Großhans
et al.
, 2005; Lin
et al.
,
2003
). In addition to regulation of
let-7
family members, several protein-
coding genes have been identified as potential direct targets of DAF-12 and
HBL-1 transcriptional control (
Niwa
et al.
, 2009; Shostak
et al.
, 2004
). How
these transcriptional networks contribute to the maintenance of undifferen-
tiated cell fates prior to expression of
let-7
is yet to be fully explored.
Mis-regulation of
let-60/RAS
contributes to the lethal phenotype of
let-7
mutants that rupture through the vulva (
Fig. 1.3
;
Johnson
et al.
, 2005
).
The 3
0
UTR of
let-60/RAS
contains multiple conserved sites of comple-
mentarity to let-7 family miRNAs (
Johnson
et al.
, 2005
). These miRNAs
act to repress expression of
let-60/RAS
in specific vulval precursor cells to
restrict RAS signaling and promote adoption of appropriate cell fates.
Remarkably, functional let-7 sites were also detected in the 3
0
UTRs of
human RAS genes. Reduced expression of mature let-7 in several types of
cancers, especially lung, is often linked to increased RAS protein (
Boyerinas
et al.
, 2010; Johnson
et al.
, 2005
). By regulating key signaling molecules and
transcription factors, let-7 family miRNAs control a large network of genes
that determine the correct timing of cell fates during worm development,
making this regulatory pathway indispensible.
4. The Role of let-7 in Development and Disease
Across Species
4.1. Stem cells and differentiation
Since several recent reviews detail the roles of mammalian let-7 miRNAs in
regulating development and disease in vertebrates, only a few select highlights
are presented here (
Boyerinas
et al.
, 2010; Ivey and Srivastava, 2010; Jiang
et al.
, 2009; Nimmo and Slack, 2009; Osada and Takahashi, 2011
). Consistent
with its role in promoting differentiated cell fates in
C. elegans,
let-7 miRNAs
are depleted frommammalian embryonic stem cells (ESCs;
Fig. 1.8
;
Bar
et al.
,
2008; Hinton
et al.
, 2010; Laurent, 2008; Suh
et al.
,2004
). This expression
