Biology Reference
In-Depth Information
stage programs to the next by downregulating key regulatory factors. Within
C
.
elegans
epidermal stem cells, microRNA
lin
-
4
successively downregulates
expression of the LIN-14 transcription factor and the LIN-28 RNA-
binding protein to promote L1/L2 and L2/L3 transitions, respectively
(
Lee et al., 1993; Moss et al., 1997; Wightman, Ha, & Ruvkun, 1993
). Sim-
ilarly, the
let
-
7
related microRNAs
mir
-
48
,
mir
-
84
, and
mir
-
241
collaborate
to downregulate the kruppel-like zinc finger protein HBL-1/hunchback
thereby catalyzing L2/L3 transitions (
Abbott et al., 2005
). Finally, the
let
-
7
microRNA downregulates the LIN-41/TRIM71 homolog and other fac-
tors to trigger L4/adult transitions (
Slack et al., 2000
). Remarkably, similar
regulatory interactions are seen driving differentiation events and stem cell
dynamics in higher animals. For example, mammalian
let
-
7
downregulates
lin
-
41
to promote neural tube closure, cell cycle exit and differentiation, and
inhibits self renewal in embryonic stem cells (
Chang et al., 2012; Maller
Schulman et al., 2008
).
The microRNAs appear to work somewhat cell autonomously, that is,
within the tissues in which they are expressed (
Zhang & Fire, 2010
). The
question arises, how are the microRNAs themselves regulated? How are
the different temporally patterned events coordinated across tissues? How
are environmental, nutritional, and growth signals integrated into develop-
mental timing circuits? And how are such events coordinated with global
transitions such as the molt cycle or dauer arrest?
3.3. DAF-12 regulates the let-7 microRNAs
Initial answers to some of these questions came with the discovery that
DAF-12 functions within the heterochronic circuit to modulate L2/L3
transitions (
Antebi, Culotti, & Hedgecock, 1998
). Mutants exhibit canon-
ical retarded heterochronic phenotypes in which they inappropriately repeat
L2 programs at the L3 stage. Such phenotypes are visible in epidermal seam
cells, intestinal nuclei, migratory cells of the gonad, and other tissues,
suggesting that DAF-12 broadly coordinates temporal programs throughout
the body. Intriguingly, the most penetrant phenotypes are provoked by
daf
-
12
(
rh61
) mutations that truncate the receptor within the LBD, while less
penetrant phenotypes are seen in null mutants that disrupt DNA and LBDs
(
Antebi et al., 2000
). Apparently, these LBD mutations abrogate ligand
binding and transcriptional activation, and instead assemble corepressor
complexes that inhibit target gene expression, thus exacerbating pheno-
types. Accordingly, removal of the corepressor
din
-
1
restores phenotypes
to that seen in the null mutants (
Ludewig et al., 2004
). This behavior is
