Biology Reference
In-Depth Information
Significantly many of the major endocrine pathways regulating dauer
also impact adult longevity and are conserved across taxa. Best known, a
modest reduction of IIS activates the DAF-16/FOXO transcription factor,
and thereby significantly extends life span in species as diverse as worms, flies,
mice, and perhaps humans (
Kenyon, 2010
). Additionally, homologs of
DAF-12 including liver-X and vitamin-D receptors have been associated
with aging in several models (
Keisala et al., 2009; Mooijaart et al., 2007
).
It is quite remarkable that IIS, TGF-
b
, and steroidal endocrine pathways
regulate major maturational transitions in worms, flies, and mammals,
revealing an ancient origin for pathways governing reproduction and
survival (
Tennessen & Thummel, 2011
)(
Fig. 7.1
B). Finally, the DA/
DAF-12 signaling mechanism has been highly conserved among nematodes,
and used to couple environmental cues to dauer diapause, and to specify
mouth dimorphisms in free living species (
Bento, Ogawa, & Sommer,
2010; Ogawa, Streit, Antebi, & Sommer, 2009
). Similarly, DA/DAF-12
regulates entry and exit from the infective stage of parasitic nematodes,
and thus could serve as a therapeutic entry point for treating pathologic
diseases (Ogawa et al., 2009;
Wang et al., 2009
).
2.3. DA biosynthetic pathway
Given the importance of the DAs in regulating DAF-12 activity and nem-
atode life history, many questions arise: how are they made, how is synthesis
regulated, and how do they govern organismal fate choice? An important
clue came from the discovery of
daf
-
9
, a cytochrome P450 critical for
DA production (
Gerisch, Weitzel, Kober-Eisermann, Rottiers, & Antebi,
2001; Jia, Albert, & Riddle, 2002; Motola et al., 2006
).
daf
-
9
mutants form
Figure 7.1
Cont'd (not shown). Upon commitment to reproductive development
DAF-12 turns on the let-7 family microRNAs, downregulating HBL-1/ZnF to catalyze L2/
L3 transitions. let-7microRNAs also feedback regulate daf-12 todiminish expression at later
stages. In unfavorable conditions, endocrine pathways are down, the unliganded receptor
forms a corepressor complex with DIN-1/SHARP, shutting downmicroRNA expression and
the developmental timer. LIN-42 and DAF-12 antagonize one another. LIN-42/PERIOD
inhibits DAF-12
'
s dauer promoting activity under mild stress, and antagonizes its
heterochronic functions in seam and gonad during reproductive development. It is
unknown if this is direct or indirect. B. Conserved regulation of reproductive signaling.
In worms, cGMP, TGF-b, and IIS regulate dafachronic acid (DA) production. In insects IIS,
TGF-b, and PTTH (prothoracicoctropic hormone) regulate ecdysteroid (Ecd) production.
Similarly in mammals, gonadotrophs (GnT), insulin/IGF, and TGF-b/activin signaling affect
production of estrogens (E) and androgens. Downstream steroid receptors promote
expression of let-7 and related microRNAs to promote maturation in various tissues.
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