Amphibians are named for their ability to undergo metamorphosis, their

appellation coming from the Greek amph' ("double") and bios ("life"). Amphibian
metamorphosis is associated with morphological changes that prepare an
aquatic organism for a primarily terrestrial existence. In urodeles (salamanders),
these cllanges include the resorption of the tail fin, the destruction of the
external gills, and a change in skin structure. In anurans (frogs and toads), the
metamorphic changes are more dramatic, with almost even organ subject to
modification. changes in amphibian metamorphosis are initiated by thyrOid
hormones such as thyroxine (T4) and trio iodothyronine (T3) that travel through
the blood to reach all the organs of the larva. When the larval organs encounter
these thyroid hormones, they can respond in any of four ways: growth, death,
remodeling, and respecification.
GROWTH OF NEW STRUCTURES The hormone tri-iodothyranine induces
certain adult-specific organs to form. The limbs of the adult frog emerge from
specific sites on the metamorphosing tadpole, and in the eye, both nictitating
membranes and eyelids emerge. Moreover, T3 induces the proliferation and
differentiation of new neurons to serve these organs. As the limbs grow out from
the body axis, new neurons proliferate and differentiate in the spinal cord. These
neurons send axons to the newly formed limb musculature.
CEll DEATH DURING METAMORPHOSIS The hormone T3 also induces
certain larval-specific structures to die. Thus, T3 causes the degeneration of the
paddle-like tail and the oxygen procuring gills that were important for larval (but
not adult) movement and respiration. While it is obvious that the tadpole'S tail
muscles and skin die, is this death murder or suicide? In other words, is T, telling
the cells to kill themselves, or is T3 telling something else to kill the cells? Recent
evidence suggests that the first part of tail resorption is caused by suicide, but
that the last remnants of the tadpole tail must be killed off by other means.
When tadpole muscle cells were injected with a dominant negative T3 receptor
(and therefore could not respond to T,), the muscle cells survived, indicating that
T3 told them to kill themselves by apoptosis.
 REMODELING DURING METAMORPHOSIS Among frogs and toads, certain
larval structures are remodeled for adult needs. Thus, the larval intestine, with
its numerous coilsfor digesting plant material, is converted into a shorter
intestine for a carnivorous diet. Schrieber and his colleagues (2005) have
demonstrated that the new cells of the adult intestine are derived from
functioning cells of the larval intestine (instead of there being a sub population of
stem cells that give rise to the adult intestine). The formation and differentiation
of this new intestinal epithelium are probably triggered by the digestion of the
old extracellular matrix by the metalloproteinase stromelysin-3, and by the new
transcription of the bmp4 and sonicc hedgehog genes.
BIOCHEMICAL RESPECIFICATION In addition to the obvious morphological
changes, important biochemical transformations occur during metamorphosis as
T3 induces a new set of proteins in existing cells. One of the most dramatic
biochemical changes occurs in the liver. Tadpoles, like most freshwater fish, are
ammonotelic-that is, they excreteammorna. Like most terrestrial vertebrates,
many adult frogs (such as the genus Rana, although not the more aquatic
Xenopus) are ureotelic: they excrete urea, which requires less water than
arrunonia excretion. During metamorphosis, the liver begins to synthesize the
enzymes necessary to create urea from carbon dioxide and alrunonia. T3 may
regulate this change by inducing a set of transcription factors that specifically
activates expression of the urea-cycle genes while suppressing the genes
responsible for arrunonia synthesis.
Hormonal control of amphibian metamorphosis. The control of
metamorphosis by thyroid hormones was first demonstrated in 1912 by
Gudernatsch, who discovered that tadpoles metamorphosed prematurely when
fed powdered horse thyroid glands. In a complementary study, Allen (1916)
found that when he removed or destroyed the thyroid rudinlent of early
tadpoles (thyroidectomy), the larvae never metamorphosed but instead grew
into giant tadpoles. Subsequent studies showed that the sequential steps of
anuran metamorphosis are regulated by increasing amounts of thyroid hormone.
 Regionally specific developmental programs. By regulating Ule amount
of T3 and TRs in their cells, the different regions of the bod y can respond to
thyroid hormones at differen t times. The type of response (proliferation,
apoptosis, differentiation, migration) is determined by other factors already
present in the different tissues. The same stimulus causes some tissues to
degenerate while stimulating others to develop and differentiate, as exemplified
by the process of tail degeneranon. Thus, thyroid hormone instructs the limb bud
muscles to grow (they die without thyroxine) while instructing the tail muscles to
undergo apoptosis.