Biology Reference
In-Depth Information
Daf genes reveals that they comprise an endocrine network converging on
DAF-12, which works as a molecular switch to mediate the choice between
arrest at diapause and progression to reproductive development (
Fig. 7.1
A).
These studies have led to a model in which environmental and physiologic
cues detected by ciliated sensory neurons in the head, are transduced through
guanylyl cyclase and various signal transduction pathways (
Fielenbach &
Antebi, 2008
). These pathways in turn impinge on two major endocrine
pathways, TGF-
b
and insulin/IGF signaling (IIS), which regulate DAF-12
steroidal signal transduction. In favorable environments, TGF-
b
and insu-
lin/IGF hormones are produced and secreted from sensory neurons (
Li,
Kennedy, & Ruvkun, 2003; Ren et al., 1996
), activating their respective sig-
nal transduction pathways in target tissues. Specifically TGF-
b
binds to its
receptors, which regulate Smad/Co-Smad transcriptional complexes (
da
Graca et al., 2004; Estevez et al., 1993; Georgi, Albert, & Riddle, 1990;
Patterson, Koweek, Wong, Liu, & Ruvkun, 1997; Ren et al., 1996
).
Insulin-like peptides bind to the insulin receptor, stimulating a PI3/AKT
kinase cascade that inhibits the DAF-16/FOXO transcription factor
(
Kimura, Tissenbaum, Liu, & Ruvkun, 1997; Li et al., 2003; Lin, Dorman,
Rodan, & Kenyon, 1997; Morris, Tissenbaum, & Ruvkun, 1996; Ogg
et al., 1997; Paradis & Ruvkun, 1998
). These two pathways converge within
steroidogenic tissues, to promote production of the cholesterol derived DAF-
12 ligands the DAs (
Motola et al., 2006
). Thereafter, DA binds to nuclear
DAF-12 expressed throughout the body to prevent dauer formation and pro-
mote reproductive development. It is postulated that ligand bound DAF-12
associates in coactivator complexes, but these remain to be identified. Con-
versely in unfavorable environments, TGF-
b
and insulin-like peptides are
downregulated, stimulating transcriptional complexes of DAF-3/Co-Smad
and DAF-5/SKI as well as DAF-16/FOXO (
da Graca et al., 2004;
Patterson et al., 1997
), which initiate specific changes toward thrifty metab-
olism and increased stress response. Biosynthesis of the DAs is repressed,
unligandedDAF-12 forms a potent repression complex with DIN-1/SHARP
corepressor, and thereby specifies the long-lived dauer stage (
Ludewig et al.,
2004
). Thus DA/DAF-12 serves as a molecular switch between reproductive
and survival modes, and is instructive in this choice: null mutations that con-
tain dual lesions affecting both DNA and LBDs result in animals unable to
enter the dauer stage (Daf-d), while LBD missense mutations cause animals
to constitutively enter the dauer stage (Daf-c) (
Antebi et al., 2000
). While
DAF-12 responsibilities during dauer formation are essential, its functions
in reproductive development are modulatory and only partly required.
