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whether puffing was a direct consequence of ecdysone activity, a series of
elegant studies byClever (in Chironomus ) and later byAshburner (in Drosophila )
tested whether protein synthesis was a requirement for the induction of puffs
by ecdysone. These studies showed that the early puffs were still induced
in the presence of protein synthesis inhibitors, while the late puffs were not.
Ashburner also found that these early puffs are autoregulatedbecause they failed
to regress when protein synthesis was inhibited. Ashburner correctly predicted
that the early puffs are direct targets of the ecdysone-bound receptor and that
the corresponding early genes encode regulatory proteins that are required for
inducing the late puffs ( Fig. 2.1 A). To this day, this conceptual framework is
referred to as the Ashburner model ( Ashburner, 1974; Ashburner, Chihara,
Meltzer, & Richards, 1974 ).
Ultimately, the studies performed by Karlson, Clever, Ashburner, and col-
leagues not only offered some of the first insights intohowgenesmay be regulated
but also produced the key ingredients for establishing an elegant and versatile
model for how steroid hormones coordinate complex developmental processes.
3. THE ECDYSONE HIERARCHY I: HORMONE ACTION AT
THE ONSET OF METAMORPHOSIS
In Drosophila , all major developmental transitions, including the molts
and the onset of metamorphosis, are triggered by major pulses of ecdysone
( Riddiford, 1993 ). Each of these pulses has its own characteristics, such as
amplitude and duration, which are largely determined by the rate and du-
ration of hormone synthesis, how efficiently the hormone is converted to its
biologically active form, and how fast it is degraded. Ecdysone is produced
and released from the prothoracic gland cells, which are part of a composite
endocrine organ called the ring gland. Once taken up by its target tissues,
ecdysone is converted to the biologically active form 20-hydroxyecdysone
(hereafter referred to as 20E) ( Gilbert, Rybczynski, & Warren, 2002 ). Like
vertebrate steroid hormones, 20E acts by binding to members of the nuclear
receptor superfamily. These are ligand-dependent transcription factors that
harbor a highly conserved DNA-binding domain (DBD) as well as less con-
served ligand-binding domain (LBD) ( King-Jones & Thummel, 2005 ). The
identification of the Drosophila ecdysone receptor gene ( EcR ) and the discov-
ery of several early ecdysone response genes established the molecular era of
ecdysone biology in the early 1990s ( Burtis, Thummel, Jones, Karim, &
Hogness, 1990; DiBello, Withers, Bayer, Fristrom, & Guild, 1991; Koelle
et al., 1991; Segraves & Hogness, 1990 ).
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