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levels are within physiological ranges, despite being much lower than
during metamorphosis.
Given the increased knowledge of the complexity of TR and TH con-
trol of transcription, there is a need to go beyond the idea that in the
absence of TH, the nonliganded receptor (aporeceptor) represses target
gene transcription and take into account the increasing evidence for
activation of gene transcription by the aporeceptor.
Consideration of each of the above concepts leads us to suggest that TH
signaling during early development is much more complex than previ-
ously envisaged, with a potential scenario of both activation and repres-
sion of target genes, notably in certain tissues, such as the developing
nervous system.
Finally, given the potentially complex role of TH during this develop-
mental period, this time window could be a period of sensitivity to en-
docrine disruption.
2. BOTH TRs AND DEIODINASES ARE EXPRESSED
DURING EMBRYOGENESIS
2.1. TRs are differentially expressed during embryonic
development
In vertebrates, different TH-binding TR isoforms have evolved, leading to
neofunctionalization for distinct TRs (
Escriva, Holland, Gronemeyer,
Laudet, & Holland, 2002
). Expression data and
in situ
screens demonstrate
that in most species harboring TR, they are expressed from the embryonic
stage onward. The expression patterns of TR show that the various isoforms
are differentially expressed during development in mammals as well as in
birds and amphibians. Schematically, two genes
TR
b
(
NR1A2
) encode the different isoforms of TRs, even if duplication or tet-
raploidization has occurred in some species. TR
a
1, TR
b
1, and TR
b
2
(
Laudet, 2011; Yaoita & Brown, 1990
) are the isoforms with both a
DNA-binding domain and a ligand-binding domain. In mouse, TRs are
expressed early in development, at least from stage E11.5 for TR
a
, and from
stage E13.5 for TR
b
(according to Allen Developing Mouse Brain Refer-
ence Atlas;
Lein et al., 2007
). TR
a
and TR
b
have distinct roles in develop-
ment, as exemplified by
Lezoualc'h, Hassan, Abdel-Tawab, Puymirat, and
Demeneix (1994)
,
Lezoualc'h et al. (1995)
, and
O'Shea et al. (2005)
.
The numerous mouse models of TR invalidation exhibit slighter devel-
opmental defects than those of hypothyroid pup. In the mouse models, as for
a
(
NR1A1
) and
TR
