Biology Reference
In-Depth Information
constitutes a cyclical molecular clock that coordinates many aspects of devel-
opment and takes about 8-10 h in
C
.
elegans
. Strikingly, several cellular pro-
grams such as seam cell division and intestinal endoreplication are closely
coordinated with cuticle synthesis and molting, and are iterated with each
larval stage (
Hedgecock & White, 1985; Sulston & Horvitz, 1977
). Even
migratory transitions in gonadal morphogenesis may be closely tied to this
clock (
Antebi et al., 1998
).
The close coordination of cellular events across tissues during the molt
cycle is suggestive of hormonal regulation. In other molting organisms such
as
Drosophila
, molting is driven by ecdysteroids working through the ecdysone
receptor and its obligate partner ultraspiracle/retinoid-X-receptor (RXR)
(
Tennessen &Thummel, 2011
). The ecdysone receptor activates downstream
transcriptional cascades including the nuclear receptors HR3, FTZ-F1, and
others.
C
.
elegans
lacks ecdysteroids and the ecdysteroid receptor. Although
steroid receptor
daf
-
12
mRNA may be expressed in a cyclical fashion
(
Merris, Wang, Soteropoulos, & Lenard, 2007
), neither the receptor nor its
ligands have an overt affect on the molt cycle except for the dauer molt. How-
ever, two other nuclear receptors, NHR-23 and NHR-25, homologs of
HR3 and FTZ-F1, respectively, oscillate with the molt cycle and are respon-
sible for molting, since their mutation results in ecdysis defects (
Asahina et al.,
2000; Gissendanner, Crossgrove, Kraus, Maina, & Sluder, 2004;
Gissendanner & Sluder, 2000; Kostrouchova, Krause, Kostrouch, & Rall,
2001
). Their ligands remain unknown, but could be sterol derivatives as cho-
lesterol deprivation results in molting defects (
Yochem, Tuck, Greenwald, &
Han, 1999
), and the mammalian homolog of NHR-23, ROR
a
,bindstoste-
rols (
Wang et al., 2010
). Alternately, they could be phospho, or sphingolipids,
since NHR-25 and homologs appear to bind these molecules (
Krylova et al.,
2005; Lee et al., 2011; Mullaney et al., 2010; Urs et al., 2007
). Another pos-
sibility is that NHR-23 and NHR-25 are not ligand gated at all, but instead
bind lipids as competency factors; in this view oscillations of other compo-
nents such as LIN-42 (below) could regulate their activity.
Remarkably the period homolog LIN-42 is also a central component of
the molt cycle.
Lin
-
42
mRNA and protein strikingly oscillate in concert
with the molt cycle with peak protein levels around the molts (
Jeon
et al., 1999; Monsalve, Van Buskirk, & Frand, 2011
). Null mutants exhibit
molting defects at all four molts, and have erratic arrhythmic molts and
extended molting quiescence, a sleep-like state during which the old cuticle
is shed (
Monsalve et al., 2011
). The
lin-42
genomic locus is complex, as it
encodes four different isoforms of diverse structure and function. The
