I. The developmental biology of leptin and leptin receptors
II. Epigenetic programming by exposure to glucocorticoids early in life
III. Molecular mechanisms of gene regulation by thyroid hormone and corticosteroid receptors during mouse and frog brain development
IV. Neuroendocrine mechanisms of developmental plasticity
V. Structural and functional evolution of the corticotropin releasing-factor family of neuropeptides
VI. Molecular basis for hormone action in amphibian metamorphosis
IV. Neuroendocrine mechanisms of developmental plasticityAlmost all animals and plants modify the expression of phenotypes in response to environmental conditions, yet we still know little about the physiological processes that allow for this flexibility, or the fitness costs and benefits of such plasticity. Environments experienced during early development can have important effects on individual fitness. For example, recent studies in mammals show that exposure to stressful environments during fetal or neonatal stages results in higher probabilities of reproductive dysfunction and adult-onset diseases. These studies suggest that activation of the maternal, fetal, or neonatal neuroendocrine stress axis profoundly influences the function of physiological systems later in life, which then predisposes these individuals to disease. The elevation in glucocorticoids in the response to stress is thought to permanently alter the function of physiological systems through their organizational effects on the developing brain.
Our work with anuran amphibians has shown that stress hormones mediate the effects of the environment on tadpole growth and the timing of metamorphosis. We found that in later-staged tadpoles, environmental stress increases hypothalamic corticotropin-releasing factor (CRF), which in turn stimulates the production of corticosteroid and thyroid hormones. This neuroendocrine pathway acts to slow growth and accelerate metamorphosis, such that tadpoles metamorphose earlier and at a smaller body size. Plasticity in developmental timing is adaptive as it increases tadpole survival; however, the long-term effects of stress-induced acceleration of metamorphosis on adult fitness have not been examined.
There are two general objectives of our studies: 1) to understand the neuroendocrine mechanisms that control developmental responses to environmental change (e.g., plasticity in the timing of amphibian metamorphosis) and 2) to develop a mechanistic basis for understanding how early life experience affects adult phenotypic expression and fitness in vertebrates. Our experiments primarily involve two anuran species, the desert-adapted Western spadefoot toad (Spea hammondii) and the aquatic South African clawed frog (Xenopus laevis). Our specific goals are:
1) To determine the role of the neuroendocrine stress axis in establishing the timing of metamorphosis in response to environmental factors such as pond drying, competition for resources and the presence of predators.
2) To determine the interaction among thyroid and corticosteroid hormones, produced in response to exposure to environmental stressors, at the level of the target tissues. We have found that corticosteroids synergize with thyroid hormone to promote tissue morphogenesis, and that the mechanistic basis for this synergy is the upregulation of thyroid hormone receptors and the enzyme that converts thyroid hormone to its most active form, deiodinase type 2. We are currently studying how the TR beta promoter is regulated by the glucocorticoid receptor. Such regulatory relationships may have broader significance; e.g., in development of the mammalian hippocampus and perhaps other brain structures.
3) To determine if variation in the tadpole's habitat generates identifiable neuroendocrine stress axis phenotypes that lead to long-term effects on growth, physiology and behavior.
4) To identify the cellular and molecular basis for the effects of stress during the larval stage on the expression of the juvenile/adult neural phenotype.
These studies use a combination of physiological, developmental and molecular biological approaches to elucidate the mechanisms of developmental plasticity.
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