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may affect cell fate via multiple mechanisms (
Lu, 2012; Luo & Semenza,
2012
), these findings support a potential role of PKM2 in the regulation
of free cellular TH to affect the metamorphic transition of these two organs.
Another factor affecting local TH levels is deiodination. TH is synthe-
sized initially as T
4
or thyroxine in the thyroid gland (
St Germain
et al., 1994
). Some T
4
in turn is converted in the thyroid gland into T
3
by 5
0
-deiodinases (
Jorgensen, 1978; St Germain et al., 1994
). Both T
3
and T
4
are then secreted into the serum and carried to target tissues
(
Hennemann & Visser, 1997; Oppenheimer et al., 1987; Ritchie et al.,
2003; Robbins, 1992; Shi, Ritchie, & Taylor, 2002; Visser, Friesema, &
Visser, 2011
). There are two families of deiodinases, 5
0
- and 5-deiodinases
(
Arrojo & Bianco, 2011; Gereben et al., 2008; St Germain et al., 1994
).
The 5
0
-deiodinases convert T4 to T3 and thus enhance TH signaling
while the 5-deiodinases inactivate both T4 and T3, thus reducing TH sig-
naling. Analysis of the expression of the 5-deiodinase gene in
X. laevis
showed that it was regulated in a organ-specific manner (
Table 10.1
)
(
St Germain et al., 1994; Wang & Brown, 1993
). It had little expression
in the intestine. In the hindlimb, it is not expressed until after limb mor-
phogenesis is completed, that is, around stage 60, when its mRNA level is
up-regulated, paralleling the increase in limb size. In contrast, relatively
high levels of its mRNA are present in the tail during premetamorphic
stages. Immediately prior to rapid tail resorption (stages 58-61), the expres-
sion of the 5-deiodinase gene is suddenly up-regulated several fold.
Its mRNA levels then return to the premetamorphic levels as tail resorp-
tion takes place after stage 61. While no detailed analyses have been done
on 5
0
-deiodinase during
X. laevis
metamorphosis, studies in
Rana catesbeiana
argue that 5
0
-deiodinase expression is also temporally regulated in different
organs such that the enzyme likely functions to increase T3 level within
the organ as metamorphosis begins (
Becker, Stephens, Davey, Schneider,
& Galton, 1997; Davey, Becker, Schneider, St Germain, & Galton, 1995
).
These findings suggest that 5 and 5
0
-deiodinases function to regulate the
levels of TH within an organ to regulate its metamorphic transformation.
While there are clearly many other factors contributing to the regulation
of TH levels within an organ, the brief summary above suggests that the
levels of both receptor and cellular free TH in individual organs during
metamorphosis contribute to the timing of tissue-specific metamorphosis.
At the mechanistic level, low levels of TH in a given organ will lead to
a high fraction of TR-RXR heterodimers in the unliganded state. This
will lead to the recruitment of HDAC-containing corepressor complexes
