Regulation of vertebrate corticotropin-releasing factor genes

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.