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display growth arrest and fail to properly remodel their organs before dying
around weaning at 3 weeks (
Mansouri, Chowdhury, & Gruss, 1998
). The
TR
a
-deficient mice exhibit similar defects: after 2 weeks, these mice (ei-
ther the TR
/
that lack only the TR
a
a
1 isoform or the TR
a
0/0 that lack
all the isoforms encoded by the TR
locus; see
Flamant et al., 2007
)be-
come progressively hypothyroid, displaying growth arrest (
Fraichard et al.,
1997; Gauthier et al., 1999, 2001
). During this period, many other phys-
iological functions are modified, correlating with organ maturation. The
increase in intestine size is characterized by an extensive development of
the villi and muscular layers (
Sirakov & Plateroti, 2011
). Metabolic con-
trols also mature and specific genes involved in
de novo
lipogenesis are
turned on preparing the soon-to-be independent pup to obtain lipids from
food. All these data therefore suggest that TR
a
gene is essential for the
transformation of a maternally dependent pup to a juvenile-autonomous
mouse. Thus, the pup diet switches for the adult diet at weaning. Then,
this switch is related to the digestive system remodeling and nervous system
development, both of these events being dependent of the TH pathway.
Overall, this mechanism is essential for the transformation of a maternally
dependent pup to a juvenile-autonomous mouse and this is highly remi-
niscent of TH-controlled metamorphosis in amphibians.
It is well known in human that THs are critical for brain development
with a particularly sensitive window of maturation at birth. In fact, TH
levels are one of the first blood parameters measured in human newborns.
The absence of TH during the very first weeks of life of a human baby
can have profound and definitive consequences on its brain maturation
(
Biswas et al., 2002; Williams, 2008
). The effects of hypothyroidism effect
on human brain development have long been studied and described (see
for an early review
Legrand, 1979
). Severe and untreated hypothyroidism
from birth, usually due to congenital hypothyroidism results in the pheno-
type known as cretinism characterized by delayed mental and physical de-
velopment, hearing and speech defects, and hypotonia (for review, see
Bernal, 2007
).
Using mouse models, it has been shown that THs and their receptors are
involved in normal brain development, particularly in the cerebellum
(
Billon, Tokumoto, Forrest, & Raff, 2001; Flamant & Samarut, 2003;
Morte, Manzano, Scanlan, Vennst
ยจ
rm, & Bernal, 2002
). The rodent cere-
bellum is composed of a small number of neuronal types (Purkinje cells,
granule cells, and GABAergic interneurons) that are morphologically and
a
