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Puzianowska-Kuznicka, & Stolow, 1996
). During embryogenesis, many
TH-inducible genes are expressed at basal levels sufficient for embry-
onic development. Once organogenesis is completed, that is, by stage
45 when feeding begins (
Nieuwkoop & Faber, 1956
), these genes are
no longer needed. The increased expression of TR and RXR genes
(e.g., RXR
a
,
Fig. 10.1
) leads to the formation of TR-RXR heterodimers
that bind to the TREs of the TH-inducible genes. In the absence of TH, the
unliganded TR recruits corepressor complexes to the genes, resulting in
the repression of these genes. Since exogenous TH can induce meta-
morphosis as early as stage 41, the model hypothesizes that this early
expression of TR is likely responsible for the tadpole competence to
undergo TH-induced metamorphosis. At the same time, gene repression
by the unliganded TR ensures proper tadpole growth and prevents pre-
mature metamorphic organ transformations, thus regulating the timing
of metamorphosis.
After stage 55, the rise of endogenously synthesized TH leads to the
binding of TH to the chromatin-bound TR, which releases the core-
pressor complexes from the target genes with concurrent recruitment of
the coactivator complexes. This results in gene activation and metamorphic
transformations in the tadpoles.
Over the years, we and others have carried out a series
in vivo
studies,
including transgenic analyses with mutant TRs to test this dual function
model (
Buchholz, Hsia, Fu, & Shi, 2003; Buchholz, Paul, & Shi, 2005;
Buchholz, Tomita, Fu, Paul, & Shi, 2004; Das, Schreiber, Huang, &
Brown, 2002; Grimaldi, Buisine, Bilesimo, & Sachs, 2013; Hasebe,
Buchholz, Shi, & Ishizuya-Oka, 2011; Nakajima & Yaoita, 2003;
Puzianowska-Kuznicka, Damjanovski, & Shi, 1997; Sachs & Shi, 2000;
Schreiber & Brown, 2003; Schreiber, Das, Huang, Marsh-Armstrong,
& Brown, 2001
). In particular, overexpression of a dominant negative
TR that lacks T3 binding ability but retains the ability to heterodimerize
with RXR and repress gene expression just like unliganded TR inhibits
TH-induced gene activation and metamorphosis in
X. laevis
(
Fig. 10.2
)
(
Buchholz et al., 2003; Das et al., 2002; Nakajima & Yaoita, 2003;
Schreiber & Brown, 2003; Schreiber et al., 2001
), indicating an essential role
of TH-bound TR in gene regulation and metamorphosis. Conversely,
overexpression of a dominant positive TR that cannot bind to TH but con-
stitutively activate TH target gene transcription leads to the upregulation of
TH response genes and tadpole metamorphosis (
Buchholz et al., 2004;
Hasebe et al., 2011
). These studies have thus demonstrated that TR is
