ReviewRegulation of vertebrate corticotropin-releasing factor genes
Introduction
“Life is stress and stress is life”.—Hans Selye, MD.
Animals must continuously adapt to internal and external environmental changes that threaten to disrupt homeostasis. Allostasis, a term first introduced by Sterling and Eyer (Sterling and Eyer, 1981), refers to the maintenance of stability through change. McEwen and colleagues (McEwen and Stellar, 1993) later applied this concept to the body’s response to stressors. The vertebrate stress response involves endocrine, behavioral, autonomic, immune, and metabolic adjustments that allow animals to adapt to challenges to homeostasis (Herman et al., 1996, Speert and Seasholtz, 2001). The perception of stressors involves multiple neural pathways that ultimately converge on peptidergic neurons located in the paraventricular nucleus (PVN) in mammals, or the anterior preoptic area (POA) in nonmammalian species. These neurons produce corticotropin-releasing factor (CRF), which is the primary neurohormone that activates the hypothalamic–pituitary–adrenal/interrenal (HPA/HPI) axis in response to a stressor. In addition to its hypophysiotropic role, CRF coordinates many aspects of the stress response such as behavioral and autonomic adjustments (see Aguilera, 1998, Ziegler and Herman, 2002, for reviews). In nonmammalian species, CRF and related peptides are potent thyrotropin (TSH) releasing factors where they regulate critical life history transitions such as amphibian metamorphosis by activating the thyroid axis (see Denver et al., 2002, De Groef et al., 2006, for reviews).
Corticotropin releasing factor is a 41-amino acid peptide first isolated from sheep hypothalamus and named for its stimulatory actions on corticotropin release by the anterior pituitary gland (Vale et al., 1981). Since then, CRF has been isolated from diverse species representing each vertebrate class except reptiles (see Lovejoy and Balment, 1999, for review). In addition to its hypophysiotropic role, CRF is widely expressed in the brain and spinal cord in both mammalian and nonmammalian species (Cummings et al., 1983, Swanson et al., 1983, Zupanc et al., 1999, Pepels et al., 2002, Lu et al., 2004, Richard et al., 2004, Yao et al., 2004, Calle et al., 2005; see Boorse and Denver, 2006, for review) where it functions as a neurotransmitter/neuronmodulator to coordinate behavioral and autonomic responses to stress (Orozco-Cabal et al., 2006; see Lovejoy and Balment, 1999, for review). Corticotropin-releasing factor and related peptides are known to play important roles in satiety and food intake (Crespi and Denver, 2004, Crespi et al., 2004; see Mastorakos and Zapanti, 2004, for review) and also influence learning and memory consolidation (see Croiset et al., 2000, Gulpinar and Yegen, 2004, Fenoglio et al., 2006, for reviews). Components of the CRF signaling pathway, including CRF, urocortins, CRF receptors and CRF binding protein are also expressed in many peripheral tissues such as the adrenal gland, spleen, heart, lung, liver, thymus, pancreas, intestines, ovary, testis, and placenta (human and higher primates) (Suda et al., 1984, Petrusz et al., 1985, Muglia et al., 1994, Boorse and Denver, 2006). Corticotropin-releasing factor and related peptides likely influence most if not all physiological functions including nervous, endocrine, vascular, cardiovascular, skeletomuscular, immune, and reproductive systems (Boorse et al., 2006; see Boorse and Denver, 2006, for review). Dysregulation of CRF and the HPA axis have been implicated in pathogenesis of several human disorders such as anxiety and depression, eating disorders, inflammatory diseases, substance abuse, and preterm parturition (see Chrousos and Gold, 1992, Majzoub et al., 1999, Tsigos and Chrousos, 2002, for reviews).
The hypophysiotropic neurons of the PVN/POA exhibit the highest level of CRF expression in vertebrate brains, and play an essential role in HPA/HPI axis regulation. In tetrapod species, CRF neurons project axons to the median eminence where neurohormones are released into the pituitary portal circulation to regulate anterior pituitary function. In teleost fishes, the hypophysiotropic CRF neurons project to the proximal pars distalis where they release their contents in close proximity to corticotrope cells (reviewed by Lovejoy and Balment, 1999). These preoptic region neurons have received greatest attention with regard to factors that regulate expression of the CRF gene (Doyon et al., 2003, Yao et al., 2004). Other brain regions, in particular limbic (amygdala, bed nucleus of the stria terminalis) and hindbrain (locus coeruleus) areas also possess CRF neurons that respond to stressors and may be influenced by glucocorticoids (see Tsigos and Chrousos, 2002, Ziegler and Herman, 2002, for reviews). This review focuses on the physiological and molecular regulation of CRF gene expression in the CNS by stressors and by glucocorticoids.
Section snippets
Central distribution of CRF neurons and basal (unstressed) expression of the CRF gene
Corticotropin-releasing factor is expressed throughout the brain of mammals in regions that include the limbic system (hippocampus, amygdala, nucleus accumbens, and bed nucleus of the stria terminalis), hypothalamus, thalamus, cerebral cortex, cerebellum, and hindbrain (Cummings et al., 1983, Swanson et al., 1983). Similar distribution patterns of CRF neurons have also been described in nonmammalian species, which suggests that this expression pattern arose early in vertebrate evolution and has
Molecular mechanisms of transcriptional regulation of CRF genes
The commonalities in the spatial, temporal and stressor-dependent expression of CRF among species suggest that the basic cis elements responsible for the regulation of CRF genes were present in the earliest vertebrates, and have been maintained by positive selection owing to the critical role that CRF plays in adaptive stress responses. We conducted a comparative genomic analysis of vertebrate CRF genes and identified several regions of strong sequence similarity (Fig. 1). Within the coding
Conclusions and future directions
Corticotropin releasing factor plays a central role in modulating the activity of the HPA/HPI axis, and in coordinating behavioral and autonomic aspects of the stress response in vertebrates. The expression of CRF in the CNS is under complex regulation by endocrine and neuronal signals. At the molecular level, the orchestrated action of multiple intracellular signaling pathways and transcription factors is required for transcriptional control of the CRF gene, but many of these pathways are
Acknowledgment
This work was supported by NSF Grant IBN 0235401 to R.J.D.
References (220)
- et al.
Expression and dexamethasone regulation of the human corticotropin-releasing hormone gene in a mouse anterior pituitary cell line
J. Biol. Chem.
(1988) Corticotropin releasing hormone, receptor regulation and the stress response
Trends Endocrinol. Metab.
(1998)- et al.
Widespread tissue distribution and diverse functions of corticotropin-releasing factor and related peptides
Gen. Comp. Endocrinol.
(2006) Nongenomic membrane actions of glucocorticoids in vertebrates
Trends Endocrinol. Metab.
(2000)Regulation of gene promoters of hypothalamic peptides
Front. Neuroendocrinol.
(2002)- et al.
Evidence that urocortin I acts as a neurohormone to stimulate alpha-MSH release in the toad Xenopus laevis
Brain Res.
(2005) - et al.
Pleiotropic signaling pathways in rapid, nongenomic action of glucocorticoid
Mol. Cell Biol. Res. Commun.
(1999) - et al.
Rapid phosphorylation of the CRE binding protein precedes stress-induced activation of the corticotropin releasing hormone gene in medial parvocellular hypothalamic neurons of the immature rat
Mol. Brain Res.
(2001) - et al.
Rest: a mammalian silencer protein that restricts sodium channel gene expression to neurons
Cell
(1995) - et al.
Ontogeny of corticotropin-releasing factor effects on locomotion and foraging in the Western spadefoot toad (Spea hammondii)
Horm. Behav.
(2004)