Biology Reference
In-Depth Information
miRNAs play a central role.
let-7
mutants on their own, as well as animals
multiply mutant for
let-7
family miRNAs, inappropriately enter lethargus as
adults and partly shed the cuticle, indicating these miRNAs engage the
mechanism to terminate molting upon reproductive maturity (
Abbott
et al., 2005; Hayes, Frand, & Ruvkun, 2006; Reinhart et al., 2000
).
Let-7 family miRNAs appear to terminate the molting cycles through
repression of
nhr-23
and
nhr-25
(
Hayes et al., 2006
); however, only the
nhr-25
3
0
UTR contains a predicted
let-7
family binding site, and whether it
is a direct target has not been established. Ties among molting, nuclear
receptors, miRNAs, and other timing pathway components, are further
strengthened by complex genetic interactions between
nhr-25
and various
heterochronic genes, and the identification of
apl-1
(amyloid precursor
protein-like-1) as a potential
nhr-25
target (
Niwa & Hada, 2010; Niwa,
Zhou, Li, & Slack, 2008
).
apl-1
functions include molting, it acts down-
stream of
let-7
, and it interacts genetically with other heterochronic pathway
members (
Hornsten et al., 2007; Niwa et al., 2008
). Many details of these
gene interactions remain unresolved.
A striking observation is that the extra molt in
let-7 mir-84
double mutants
occurs synchronously in the adult population (
Hayes et al., 2006
), indicating a
timing mechanism at work. This finding emphasizes key questions—what
paces the molts, and how are the stage-specific programs integrated with
the molting timer? Exciting recent work again implicates the heterochronic
gene network, this time through
lin-42
(
Monsalve, Van Buskirk, & Frand,
2011
), a gene first identified by mutations that cause a precocious
heterochronic phenotype (
Jeon, Gardner, Miller, Deshler, &Rougvie, 1999
).
8. LIN-42: A LINK BETWEEN MOLTING AND
DEVELOPMENTAL DECISIONS
LIN-42 provides a remarkable link to biological timing mechanisms in
flies and mammals: it is the nematode homolog of the Period family of cir-
cadian rhythm proteins.
lin-42
and Per genes exhibit an intriguing parallel in
regulation: their mRNA and protein levels oscillate over biologically perti-
nent time scales. LIN-42 levels fluctuate with the molting cycle (
8-10 h at
25
C) while PER levels are synchronized with the 24-h clock (
Hardin,
Hall, & Rosbash, 1990; Jeon et al., 1999; Shearman, Zylka, Weaver,
Kolakowski, & Reppert, 1997; Sun et al., 1997; Tei et al., 1997;
Tennessen, Gardner, Volk, & Rougvie, 2006
). As a result of its phenotypes
and expression patterns,
lin-42
function has been most
studied in a
