Corticotropin-releasing hormone (CRH) plays multiple roles in vertebrate species. In mammals, it is the major hypothalamic releasing factor for pituitary adrenocorticotropin secretion, and is a neurotransmitter or neuromodulator at other sites in the central nervous system. In non-mammalian vertebrates, CRH not only acts as a neurotransmitter and hypophysiotropin, it also acts as a potent thyrotropin-releasing factor, allowing CRH to regulate both the adrenal and thyroid axes, especially in development. The recent discovery of a family of CRHlike peptides suggests that multiple CRH-like ligands may play important roles in these functions. The biological effects of CRH and the other CRH-like ligands are mediated and modulated not only by CRH receptors, but also via a highly conserved CRH-binding protein (CRH-BP). The CRH-BP has been identified not only in mammals, but also in non-mammalian vertebrates including fishes, amphibians, and birds, suggesting that it is a phylogenetically ancient protein with extensive structural and functional conservation. In this review, we discuss the biochemical properties of the characterized CRH-BPs and the functional roles of the CRH-BP. While much of the in vitro and in vivo data to date support an 'inhibitory' role for the CRH-BP in which it binds CRH and other CRH-like ligands and prevents the activation of CRH receptors, the possibility that the CRH-BP may also exhibit diverse extra-and intracellular roles in a cellspecific fashion and at specific times in development is also discussed.

Corticosteroids, the primary circulating vertebrate stress hormones, are known to potentiate the actions of thyroid hormone in amphibian metamorphosis. Environmental modulation of the production of stress hormones may be one way that tadpoles respond to variation in their larval habitat, and thus control the timing of metamorphosis. Thyroid hormone and corticosteroids act through structurally similar nuclear receptors, and interactions at the transcriptional level could lead to regulation of common pathways controlling metamorphosis. To better understand the roles of corticosteroids in amphibian metamorphosis we analyzed the developmental and hormonedependent expression of glucocorticoid receptor (GR) mRNA in the brain (diencephalon), intestine and tail of Xenopus laevis tadpoles. We compared the expression patterns of GR with expression of thyroid hormone receptor beta (TR ). In an effort to determine the relationship between nuclear hormone receptor expression and levels of ligand, we also analyzed changes in wholebody content of 3,5,3 -triiodothyronine (T 3 ), thyroxine, and corticosterone (CORT). GR transcripts of 8, 4 and 2 kb were detected in all tadpole tissues, but only the 4 and 2 kb transcripts could be detected in embryos. The level of GR mRNA was low during premetamorphosis in the brain but increased significantly during prometamorphosis, remained at a constant level throughout metamorphosis, and increased to its highest level in the juvenile frog. GR mRNA level in the intestine remained relatively constant, but increased in the tail throughout metamorphosis, reaching a maximum at metamorphic climax. The level of GR mRNA was increased by treatment with CORT in the intestine but not in the brain or tail. TR mRNA level increased in the brain, intestine and tail during metamorphosis and was induced by treatment with T 3 . Analysis of possible crossregulatory relationships between GRs and TRs showed that GR mRNA was upregulated by exogenous T 3 (50 nM) in the tail but downregulated in the brain of premetamorphic tadpoles. Exogenous CORT (100 nM) upregulated TR mRNA in the intestine. Our findings provide evidence for tissuespecific positive, negative and crossregulation of nuclear hormone receptors during metamorphosis of X. laevis. The synergy of CORT with T 3 on tadpole tail resorption may depend on the accelerated accumulation of GR transcripts in this tissue during metamorphosis, which may be driven by rising plasma thyroid hormone titers.

No abstract

Hypothyroidism reduces GH synthesis and release in several mammalian species, in which thyroid hormone directly stimulates GH gene transcription. In contrast, hypothyroidism stimulates GH secretion in birds, in which thyroid hormone directly inhibits pituitary GH release. We have, therefore, investigated the effects of thyroid status on the accumulation of newly synthesized GH in the pituitaries of 8- to 10-week-old Leghorn cockerels in vitro and in vivo. The incorporation of [35S]methionine into immunoprecipitable GH ([35S] GH) was increased, over a 4-h incubation period, in glands from birds made hypothyroid by injections of methimazole (50 mg/kg day for 10 days) in comparison with glands from vehicle-injected controls. Treatment with tri-iodothyronine (T3, 100 micrograms/kg per day for 10 days) in vivo did not significantly alter the accumulation of [35S]GH in vitro but did block the release of [35S]GH in response to a GH secretagogue (thyrotrophin-releasing hormone; exposure to 280 nmol/l for 30 min) and reduced immunoassayable pituitary GH content. Pretreatment of glands from euthyroid birds with T3 (100 nmol/l) in vitro (for 20 h) reduced the basal accumulation of [35S]GH as well as that induced by another GH secretagogue (GH-releasing factor; 100 nmol/l) during a 6-h labelling period. These results show that, unlike the generally stimulatory action of thyroid hormone in mammals, in birds, T3 exerts a direct inhibitory effect on the accumulation of newly synthesized pituitary GH.

No abstract