Biology Reference
In-Depth Information
The synthesis of THs is a complex pathway that occurs in the thyroid
gland (
Fig. 14.1
). During this process, a large protein, thyroglobulin, is used
as a reservoir of tyrosine residues on which iodine atoms are coupled by
thyroperoxidase (TPO). These mono- or di-iodotyrosines are then coupled
to form either T4 (mainly) or T3 (
Dunn & Dunn, 1999; Gavaret,
Cahnmann, & Nunezet, 1981
). The newly synthesized molecules are then
separated from the matrix protein, secreted and transported in the blood by
various carrier, or transporter proteins that are more or less specific for THs
(for review, see
Visser, Friesema, & Visser, 2011
). Several molecules, known
as goitrogens, are widely used to specifically block THs synthesis pathway.
These chemicals mainly act by inhibiting the iodine uptake in the thyroid
gland or by the binding of iodine to the tyrosine residues. For instance,
methimazole or propylthiouracil inhibits TPO and specifically its action
in oxidizing the iodine anion before its incorporation. In contrast, sodium
perchlorate inhibits the sodium-dependant iodide transporter known as NIS
that is required for iodine uptake in the thyrocyte (
Opitz et al., 2006
).
TH binds to thyroid hormone receptors (TRs) that are members of the
nuclear receptor family. There are two TRs genes TR
in most
vertebrates that originate from an ancestral vertebrate duplication and are
thus considered as paralogous genes (
Escriva, Manzon, Yousson, &
Laudet, 2002; Paris & Laudet, 2008
). These receptors act as ligand-
dependant transcription factors regulating negatively the transcription of
their target genes in the absence of TH and positively in their presence
(
Buchholz, Paul, Fu, & Shi, 2006
). In the past two decades, the establish-
ment of several TR mutant mice line provided powerful tools to investigate
the role of TH particularly during development and homeostasis in mam-
mals (
Flamant, Gauthier, & Samarut, 2007; Flamant & Samarut, 2003
).
It is important to note that in all vertebrates the amount of TH produced
by the thyroid gland is controlled by the hypothalamic-pituitary-thyroid
(HPT) axis (
Chiamolera & Wondisford, 2009
). The thyrotropin-releasing
hormone (TRH) production by the hypothalamus is controlled by environ-
mental cues and regulates the levels of thyroid-stimulating hormone (TSH)
production by the pituitary, which in turn stimulates TH production by the
thyroid. In turn, T3 has long been known to control its own production via
negative feedback loops acting at the levels of TRH and TSH production in
the hypothalamus and pituitary, respectively. The molecular control of these
feedback loops is far from being well understood and is currently deciphered
in mammals using genetically modified mouse models. Although it is out of
the scope of this review, it is important to mention that in amphibians it is
a
and TR
b
