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Hormonal control of development during the human perinatal period is critically important and complex with multiple hormones regulating fetal growth, brain development, and organ maturation in preparation for birth. Genetic and environmental perturbations of such hormonal control may cause irreversible morphological and physiological impairments and may also predispose individuals to diseases of adulthood, including diabetes and cardiovascular disease. Endocrine and molecular mechanisms that regulate perinatal development and that underlie the connections between early life events and adult diseases are not well elucidated. Such mechanisms are difficult to study in uterus-enclosed mammalian embryos because of confounding maternal effects. To elucidate mechanisms of developmental endocrinology in the perinatal period, Xenopus laevis the African clawed frog is a valuable vertebrate model. Frogs and humans have identical hormones which peak at birth and metamorphosis, have conserved hormone receptors and mechanisms of gene regulation, and have comparable roles for hormones in many target organs. Study of molecular and endocrine mechanisms of hormone-dependent development in frogs is advantageous because an extended free-living larval period followed by metamorphosis (1) is independent of maternal endocrine influence, (2) exhibits dramatic yet conserved developmental effects induced by thyroid and glucocorticoid hormones, and (3) begins at a developmental stage with naturally undetectable hormone levels, thereby facilitating endocrine manipulation and interpretation of results. This review highlights the utility of frog metamorphosis to elucidate molecular and endocrine actions, hormone interactions, and endocrine disruption, especially with respect to thyroid hormone. Knowledge from the frog model is expected to provide fundamental insights to aid medical understanding of endocrine disease, stress, and endocrine disruption affecting the perinatal period in humans.
Fig. 1.
Hormone structures and developmental profiles. (A) Cortisol is released from the adrenal gland in humans and fish, whereas corticosterone is released in mice and frogs. Both cortisol and corticosterone bind the two GC receptors, Type I and Type II with high affinity. (B) Thyroxine (T4) is the prohormone form of TH, and tri-iodothyronine (T3) is the active form, and the structure of these hormones is identical among all vertebrates. Two TH receptors exist in all vertebrates, TH receptor alpha and TH receptor beta (TRα and TRβ), and both receptors bind T3 with 10-fold higher affinity than T4. (C) Diagram of developmental profiles of hormone levels in the blood in humans and frogs. The plasma levels of TH and GCs peak in the blood at birth in humans and metamorphosis in frogs. Profile curves were extracted from (Carr et al., 1981, Scottish Preterm Thyroid Group, 2004, Jolivet Jaudet and Leloup Hatey, 1984, Leloup and Buscaglia, 1977 and Tata, 1993).
Fig. 2.
Structure and conservation of TH and GC nuclear receptors. (A) The receptors for GCs and TH belong to the family of ligand-activated nuclear receptors and share a common structure with a variable A/B transactivation domain, the conserved C domain or DNA binding domain (DBD), the hinge region (D domain), and the E/F ligand binding domain (LBD) where co-repressors and co-activators also bind. (B) The percent similarity comparisons in amino acid sequence between human, mouse, frog (Xenopus laevis), and zebrafish (Danio rerio) were done using full-length protein sequences. For each comparison, the sequence divergences are predominantly due to disparity in the A/B domains rather than the conserved DBD or LBD.
Fig. 3.
Hormone target organs in common at birth and metamorphosis. Many organs require GC and TH hormone signaling for proper development in humans and frogs (Brown and Cai, 2007, Dodd and Dodd, 1976, Forhead and Fowden, 2014, Fowden and Forhead, 2013 and Liggins, 1994).
Fig. 4.
Dual function model for the role of TH receptors in gene regulation and development. Unliganded TH receptor: in the absence of TH, TH receptors inhibit TH-dependent differentiation by forming heterodimers with RXR (retinoid X receptor), binding promoter or enhancer regions of TH-response genes, recruiting co-repressors to deacetylate histones, and repressing gene expression. NCoR-nuclear co-repressor, HDAC3-histone deacetylase 3, TBL1- transducinbeta-like protein 1, GPS2-G protein pathway suppressor 2. Liganded TH receptor: In the presence of TH, TH receptors initiate TH-dependent development by forming heterodimers with RXR (retinoid X receptor), binding promoter or enhancer regions of TH-response genes, recruiting co-activators to acetylate histones, and inducing gene expression. SRC-steroid receptor co-activator, p300/CBP-cAMP response element binding protein, HAT-histone acetytransferase.
