Review
Regulation of vertebrate corticotropin-releasing factor genes

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Abstract

Developmental, physiological, and behavioral adjustments in response to environmental change are crucial for animal survival. In vertebrates, the neuroendocrine stress system, comprised of the hypothalamus, pituitary, and adrenal/interrenal glands (HPA/HPI axis) plays a central role in adaptive stress responses. Corticotropin-releasing factor (CRF) is the primary hypothalamic neurohormone regulating the HPA/HPI axis. CRF also functions as a neurotransmitter/neuromodulator in the limbic system and brain stem to coordinate endocrine, behavioral, and autonomic responses to stressors. Glucocorticoids, the end products of the HPA/HPI axis, cause feedback regulation at multiple levels of the stress axis, exerting direct and indirect actions on CRF neurons. The spatial expression patterns of CRF, and stressor-dependent CRF gene activation in the central nervous system (CNS) are evolutionarily conserved. This suggests conservation of the gene regulatory mechanisms that underlie tissue-specific and stressor-dependent CRF expression. Comparative genomic analysis showed that the proximal promoter regions of vertebrate CRF genes are highly conserved. Several cis regulatory elements and trans acting factors have been implicated in stressor-dependent CRF gene activation, including cyclic AMP response element binding protein (CREB), activator protein 1 (AP-1/Fos/Jun), and nerve growth factor induced gene B (NGFI-B). Glucocorticoids, acting through the glucocorticoid and mineralocorticoid receptors, either repress or promote CRF expression depending on physiological state and CNS region. In this review, we take a comparative/evolutionary approach to understand the physiological regulation of CRF gene expression. We also discuss evolutionarily conserved molecular mechanisms that operate at the level of CRF gene transcription.

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.

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