Genetic analyses show frog metamorphosis requires thyroid hormone signaling increased by glucocorticoid receptor...

Virtually all vertebrates experience a post-embryonic developmental transition dependent on thyroid and corticosteroid hormones. Molecular and developmental actions of these hormones are highly conserved among vertebrates, but the significance and nature of hormone interaction regulating the process has not been well understood. Frog metamorphosis is an excellent model for hormones in development due to the dramatic, sensitive, and readily manipulable changes occurring during the 2-week transition. In frogs, thyroid hormone initiates metamorphosis, and corticosteroid hormones accelerate thyroid hormone-induced changes. Sorting out precise roles of corticosteroid hormones and receptors has been challenging due to lack of genetic models. Here, we review results from four genetic frog models affecting corticosteroid signaling. Tadpoles with adrenocorticotropic hormone and glucocorticoid receptor mutations have low to no corticosteroid signaling and die during metamorphosis, but exogenous thyroid hormone allows them to complete metamorphosis. Tadpoles with 21-hydroxylase mutations survive through metamorphosis, despite lack of 21-hydroxyated corticosteroids, via corticosteroid signaling from high levels of low affinity steroid biosynthesis intermediates. Tadpoles with mineralocorticoid receptor mutations have no apparent metamorphic phenotype. These results indicate that survival through metamorphosis requires activation of the glucocorticoid receptor with no requirement for mineralocorticoid receptor activation. Further, these results show that the only vital role of corticosterone signaling through the glucocorticoid receptor is increasing tissue sensitivity to thyroid hormone thereby enabling endogenous thyroid hormone levels to accomplish metamorphic completion. These hormone interactions observed in frogs will inform similar examinations in other groups where developmental transitions may be highly influenced by such interactions but remain uncharacterized.