Biology Reference
In-Depth Information
shortest isoform appears to be mainly responsible for molting, since its
expression can restore molt defects in the background of
lin
-
42
loss-of-
function mutants, and forced overexpression can induce erratic molts and
quiescence. The cyclical pattern of expression and function of
lin
-
42
resem-
bles that of circadian timers, with an 8-10 h cycle instead of 24 h. Interest-
ingly, in mammals ROR
a
is an integral component of the circadian clock
and is regulated by the
lin
-
42
homolog period (
Ranhotra, 2012
).
There are other intriguing parallels between the molt cycle and circadian
cycles: the molt cycle begins with feeding behavior, anabolic processes and
activity, comparable to the day period. Thereafter worms enter lethargus, a
sleep-like quiescent state during which there is a cessation of feeding and
movement, and reserves are drawn upon for energy. Concurrently, the
old cuticle is shed and the new one laid down, coupled to concerted growth.
Both molt and circadian cycles likely entail negative feedback loops although
the functional relationships between the
C
.
elegans
molting regulators
lin
-
42
,
nhr
-
23
, and
nhr
-
25
are poorly understood. All three gene products are reg-
ulated in a cyclical fashion, but whether they cross regulate one another's
activity is unknown. Generally speaking the molecular mechanisms under-
lying molting and circadian clocks might inform one another, and both may
deploy nuclear receptor cascades organized in feedback loops that are reg-
ulated by
lin
-
42
/period.
Although the function of heterochronic and molting timers are some-
what separable, there is also considerable overlap as already described for
lin
-
42
. Other examples include NHR-25 whose major function is to drive
the molt cycle, but mutants also display complex heterochronic phenotypes
suggestive of defects in the larval to adult switch (
Hada et al., 2010
). Another
gene implicated in molting, the amyloid precursor protein homolog
apl
-
1
,
can suppress some of the lethality and heterochronic phenotypes of
let
-
7
(
Hornsten et al., 2007; Niwa, Zhou, Li, & Slack, 2008; Wiese, Antebi, &
Zheng, 2010
). A component of SCF ubiquitin ligases, the FBXO11 homo-
log
dre
-
1
, works in both developmental timing and molting pathways
(
Fielenbach et al., 2007
). Conversely, several genes in the heterochronic
pathway oscillate with the molt cycle including the pri-microRNA form
of
let
-
7
and possibly
daf
-
12
(
Merris et al., 2007; Van Wynsberghe et al.,
2011
).
let
-
7
and related microRNAs as well as many other heterochronic
genes affect the terminal molt (
Ambros & Horvitz, 1984; Reinhart et al.,
2000
). In particular retarded heterochronic mutants often have supernumer-
ary molts, while precocious mutants cease molting one or two stages earlier
than normal. Evidence suggests that the
let
-
7
microRNAs may play a role in
