46 research outputs found
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Molecular mechanisms of crosstalk between thyroid hormones and estrogens
Purpose of review
Novel analyses of the relations between thyroid hormone
receptor signaling and estrogen receptor—dependent
mechanisms are timely for two sets of reasons. Clinically,
both affect mood and foster neuronal growth and
regeneration. Mechanistically, they overlap at the levels of
DNA recognition elements, coactivators, and signal
transduction systems. Crosstalk between thyroid hormone
receptors and estrogen receptors is possibly important to
integrate external signals to transcription within neurons.
Recent findings
It has been shown that reproductive functions, including
behaviors, driven by estrogens can be antagonized by
thyroid hormones, and it has been argued that such
crosstalk is biologically adaptive to ensure optimal
reproduction. Transcriptional facilitation during transient
transfunction studies show that the interactions between
thyroid receptor isoforms and estrogen receptor isoforms
depend on cell type and promoter context. Overall, this
pattern of interactions assures multiple and flexible means
of transcriptional regulation. Surprisingly, in some brain
areas, thyroid hormone actions can synergize with
estrogenic effects, particularly when nongenomic modes of
action are considered, such as kinase activation, which, as
has been reported, affect later estrogen receptor—induced
genomic events.
Summary
In summary, recent work with nerve cells has contributed to
a paradigm shift in how the molecular and behavioral
effects of hormones which act through nuclear receptors
are viewed
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New concepts in the neuroendocrine regulation of female reproductive behavior
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Estrogens and thyroid hormone: Non-genomic effects are coupled to transcription.
Estrogens and thyroid hormones are regulators of important diverse physiological processes such as reproduction,
thermogenesis, neural development, neural differentiation and cardiovascular functions. Both are ligands for receptors
in the nuclear receptor superfamily, which act as ligand-dependent transcription factors, regulating transcription.
However, estrogens and thyroid hormones also rapidly (within minutes or seconds) activate kinase cascades and calcium increases, presumably initiated at the cell membrane. We discuss the relevance of both modes of hormone action, including the membrane estrogen receptor, to physiology, with particular reference to lordosis behavior. We first showed that estrogen restricted to the membrane can, in fact, lead to subsequent increases in transcription from a consensus estrogen response element-based reporter in the neuroblastoma cell line, SK-N-BE(2)C. Using a novel hormonal paradigm, we also showed that the activation of protein kinase A, protein kinase C, mitogen activated protein kinase and increases in calcium
were important in the ability of the membrane-limited estrogen to potentiate transcription. We discuss the source of calcium important in transcriptional potentiation. Since estrogens and thyroid hormones have common effects on neuroprotection, cognition and mood, we also hypothesized that crosstalk could occur between the rapid actions of thyroid hormones and the genomic actions of estrogens. In neural cells, we showed that triiodothyronine acting rapidly via MAPK can increase transcription by the nuclear estrogen receptor ERa from a consensus estrogen response element, possibly by the phosphorylation of the ERa. Novel mechanisms that link signals initiated by hormones from the membrane to the nucleus are physiologically relevant and can achieve neuroendocrine integratio
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Differential crosstalk between estrogen receptor (ER) alpha and ER beta and the thyroid hormone receptor isoforms results in flexible regulation of the consensus ERE
Crosstalk between nuclear receptors is important for conversion of external and internal stimuli to a physiologically meaningful response by cells. Previous studies from this laboratory have demonstrated crosstalk between the estrogen (ER) and thyroid hormone
receptors (TR) on two estrogen responsive physiological promoters, the preproenkephalin and oxytocin receptor gene promoter. Since ERa and ERb are isoforms possessing overlapping and distinct transactivation properties, we hypothesized that the interaction of ERa and b with the various TR isoforms would not be equivalent. To explore this hypothesis, the consensus estrogen response element (ERE)derived from the Xenopus vitellogenin gene is used to investigate the differences in interaction between ERa and b isoforms and the different TR isoforms in fibroblast cells. Both the ER isoforms transactivate from the consensus ERE, though ERa transactivates to a
greater extent than ERb. Although neither of the TRb isoforms have an effect on ERa transactivation from the consensus ERE, the liganded TRa1 inhibits the ERa transactivation from the consensus ERE. In contrast, the liganded TRa1 facilitates ERb-mediated transactivation. The crosstalk between the TRb isoforms with the ERa isoform, on the consensus ERE, is different from that with the ERb isoform. The use of a TRa1 mutant, which is unable to bind DNA, abolishes the ability of the TRa1 isoform to interact with either of the ER isoforms. These differences in nuclear receptor crosstalk reveal an important functional difference between isoforms, which provides a novel mechanism for neuroendocrine integration
Sexual differentiation of the human brain in relation to gender-identity, sexual orientation, and neuropsychiatric disorders.
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Mechanisms of steroid hormone action on developing and adult hypothalamic nerve cells: biophysical and molecular studies relevant for hormone-dependent behaviors
Aging of the Brain
An increasing number of persons live for nine or more decades and enjoy the benefits of a well-functioning brain until the end of their life. In that respect, the cognitive performance in later life and the quality maintenance of the brain are amazing biological phenomena. Since most nerve cells are generated during pregnancy and have to survive an active lifetime, the brain has to be endowed with a maintenance machinery of surprising long-term quality. During successful, that is, non-pathological, aging in most brain regions, there is very little or no evidence for a decrease in numbers of neurons. In some brain structures, a limited reduction of nerve cells may occur, but it is generally conceived that aging and aging-related cognitive impairments are not the result of massive cell loss but rather the result of synaptic changes, receptor dysfunction or signaling deficits, and metabolic decline. Besides, nerve cell loss during normal aging may be compensated by synaptogenesis, dendritic branching, or in certain brain structures like dentate gyrus by neurogenesis from progenitor stem cells. Yet most human individuals suffer from a mild but life-disturbing condition we call aging-related memory impairment (AMI). In this chapter, some of the mechanisms will be shortly explored that are considered to be causal to non-pathological deterioration of cognitive faculties. In particular several cellular and molecular neuronal changes will be addressed that occur during aging, the consequences for interneuronal communication and membrane potential, the blood supply to the brain and cerebrovascular condition, and some observations on the protective neuroimmune system of the brain