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Brown, 1993; Wang et al., 2008; Wong & Shi, 1995
). Similarly, in the tail,
the genes are expressed at low levels until stage 62 when they are
up-regulated, coinciding with the rapid tail resorption, while in the intes-
tine, high levels of TR and RXR mRNAs are present during tissue remo-
deling (stages 58-66) (
Table 10.1
)(
Wang & Brown, 1993; Wong & Shi,
1995
). Thus, the levels of TR-RXR heterodimers likely help to determine
temporal regulation of the changes in individual organs.
In the absence of TH, the presence of TR-RXRin a givenorgan can act to
prevent precocious metamorphosis of the organ, thus ensuring its function in
the developing tadpoles. TH levels in an organ is affected several mechanisms.
The first is the circulating plasma levels of TH, governed mainly by the
production of TH in the thyroid gland (
Table 10.1
and
Fig. 10.1
)
(
Leloup & Buscaglia, 1977
). Secondly, the levels of cellular TH could be
affected by cellular proteins that bind TH, that is, cytosolic thyroid hormone
binding proteins (CTHBPs). Finally, the metabolic conversion of T
4
to T
3
and/or the inactivation of both hormones may be an important step in
regulating the levels of functional TH within an organ.
While all organs are exposed to the same circulating plasma TH, once
TH enters the cytoplasm, it is likely to CTHBPs (
Ashizawa & Chen,
1992; Barsano & Groot, 1983; Shi, Liang, Parkison, & Cheng, 1994;
Yamauchi & Tata, 1994
). In general, CTHBPs are multi-functional proteins
that serve one or more other roles (e.g., pyruvate kinase, myosin light chain
kinase, and disulfide isomerase) and bind TH with 10-100-fold weaker
affinity than the nuclear TRs. The exact roles of these CTHBPs in TH signal
transduction are still unclear. These proteins could participate in TH import
from the extracellular medium, intracellular TH metabolism, and transport
to the nucleus, or serve as a buffer to modulate intracellular free TH con-
centrations. Studies on the human M2 pyruvate kinase (PKM2) have shown
that over-expression of the protein leads to an inhibition of TH-dependent
transcriptional activation by TR in a tissue culture cell line (
Ashizawa &
Chen, 1992
). Interestingly, analysis of the expression of the frog PKM2
in the tail, limb, and intestine revealed that the intestine had very low but
relatively constant levels of its mRNA during development (
Shi et al.,
1994
). In contrast, the PKM2 expression in the tail and hindlimb was dras-
tically altered during metamorphosis. Low levels of PKM2 mRNA were
present in either the hindlimb during morphogenesis (stages 54-56) or tail
during resorption (stages 62-64) (
Table 10.1
). Interestingly, PKM2 mRNA
levels increased dramatically in the growing hindlimb and decreased precip-
itously in the resorbing tail. Thus, while recent studies suggest that PKM2
