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in the presence of the deiodinase inhibitor iopanoic acid ( Brown, 2005 ).
Dio2 mRNA expression showed a progressive decline in the brain through-
out metamorphosis, while brain Dio3 mRNA increased during late
prometamorphosis and metamorphic climax ( Hogan, Crump, Duarte,
Lean, & Trudeau, 2007 ). TH induces cell proliferation in the early
prometamorphic tadpole brain, but cells of the neurogenic zone become
refractory to TH action on cell proliferation as metamorphic climax
approaches, which may be explained by the temporal patterns of Dio2
and Dio3 expression and actions ( Cai & Brown, 2004; Denver, Hu,
Scanlan, & Furlow, 2009 ).
THregulates the expressionof the Dio2 and Dio3 genes. Dio3 appears tobe a
direct T 3 response gene based on its T 3 response kinetics and the resistance of
its upregulation to protein synthesis inhibition ( Becker, Schneider, Davey, &
Galton, 1995; Das, Heimeier, Buchholz, & Shi, 2009; Denver, Pavgi, & Shi,
1997; Hogan et al., 2007; Kawahara, Gohda, & Hikosaka, 1999; St Germain
et al., 1994; Wang & Brown, 1993 ). TH positively regulates 5 0 -deiodinase ac-
tivity and Dio2 mRNA in tadpoles ( Brown, 2005; Buscaglia et al., 1985;Hogan
et al., 2007 ). However, unlike Dio3 , which is an early T 3 response gene, Dio2
exhibits delayed response kinetics; the gene was not isolated in screens for early
response, direct TR target genes in Xenopus tadpole tissues ( Bonett et al.,
2010; Brown, 2005; Buchholz, Heimeier, Das, Washington, & Shi, 2007;
Das et al., 2006 ). The dependence of Dio2 expression on THmay vary among
tissues. Tissues in which cell proliferation occurs as an early response to TH
constitutively express relatively high levels of Dio2 (e.g., neurogenic zones
of the brain and spinal cord, limb buds); whereas, in tissues that transform later,
Dio2 is upregulated by TH ( Cai & Brown, 2004 ). Treatment of early
prometamorphic tadpoles with T 4 can induce cell proliferation in these
tissues, which can be blocked by the deiodinase inhibitor iopanoic acid ( Cai
&Brown, 2004 ). Dio2 mRNAinbrainand spinal corddeclines atmetamorphic
climax, as does TH-dependent cell proliferation ( Cai &Brown, 2004; Denver
et al., 2009 ). While the decline in Dio2 mRNA may be permissive for the
reduction in TH-dependent cell proliferation in the brain, it does not alone
explain why the brain becomes refractory to TH action since treatment with
T 3 couldnot increase cell proliferation (whichnormally declines) as the animals
approach metamorphic climax ( Denver et al., 2009 ). The decline in cell pro-
liferation is likely due to processes, likely under TH control, that lead to a re-
duction in the stem cell/progenitor pool in the ventricular/subventricular
zones of the tadpole brain. Dio2 expression then appears in late-responding
tissues such as the intestine, tail, and anterior pituitary and may be induced at
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