How Clocks and Hormones Act in Concert to Control the Timing of Insect Development - Current Topics in Developmental Biology - page 24

the source of this metamorphosis-blocking activity, now known as JH, back
to a pair of small glands, the corpora allata , which are connected to the brain
by a nerve. However, the prospects for identifying the chemical nature of
the JHs were limited by the fact that the corpora allata remained the sole
known JH source for many years, and that these glands only produced
minute amounts of the hormone. This situation changed when Carrol
M. Williams identified large amounts of JH in the abdomens of Cecropia
and Cynthia moths ( Williams, 1963 ), which spurred a new era of JH research
that led to the identification of the chemical structure of JH (now known
as JH-I) by R¨ ller, Dahm, Sweeley, and Trost (1967) a few years later.
The hormone turned out to be an unusual lipophilic sesquiterpenoid deriv-
ative of farnesoic acid, not dissimilar from retinoic acid, a metabolite of
vitamin A that acts as a morphogen in vertebrate development. The similar-
ity to retinoic acid spawned the idea that JH binds to USP, the insect ortho-
log of the vertebrate nuclear receptor for 9- cis -retinoic acid, RXR a . The
compelling concept that USP could double-function as JH receptor and
as heterodimeric partner for EcR to form the functional EcR has lost some
of its attractiveness due to the difficulty of identifying natural JH ligands for
USP. Instead, methyl farnesoate, a compound secreted from Drosophila cor-
pora allata and required for normal development, was shown to bind to USP
with nanomolar affinities ( Jones et al., 2010; Jones, Jones, Teal, Sapa, &
Wozniak, 2006 ).
Due to the lack of a receptor, the mode of JH action remained unclear for
many years. The first insight into the nature of the JH receptor was the iden-
tification of the Drosophila Met mutant ( Methoprene-tolerant ) in a screen aimed
at identifying Drosophila mutants resistant to the JH mimic Methoprene,
which normally causes toxicity and morphological changes when applied
topically to third instar larvae ( Wilson & Fabian, 1986 ). However, Met
mutant flies displayed mainly normal development and were homozygous
viable, which was inconsistent with the idea that Met represented a bona
fide JH receptor, unless there was some functional redundancy with another
protein. Indeed, the later identification of a bHLH-PAS paralog of Met,
Germ cell-expressed (Gce), led to the discovery that Gce and Met can
form heterodimers ( Godlewski, Wang, & Wilson, 2006 ) and are partially
redundant in transducing JH signaling ( Abdou et al., 2011; Baumann,
Barry, Wang, Fujiwara, & Wilson, 2010 ). Similar to Met , gce mutants have
increased resistance to Methoprene, but are homozygous viable, while dou-
ble mutants homozygous for gce and Met die as prepupae. Both proteins were
shown to bind to JH with high affinity ( Charles et al., 2011; Miura, Oda,
Makita, & Chinzei, 2005 ), corroborating the idea that both Gce and Met