Abstract
Corticotropin-releasing hormone (CRH) contributes crucially to the regulation of central and peripheral responses to stress. Because of the importance of a finely tuned stress system, CRH expression is tightly regulated in an organ- and brain region-specific manner. Thus, in the hypothalamus, CRH is constitutively expressed and this expression is further enhanced by stress; however, the underlying regulatory mechanisms are not fully understood. The regulatory region of the crh gene contains several elements, including the cyclic-AMP response element (CRE), and the role of the CRE interaction with the cyclic-AMP response element binding protein (CREB) in CRH expression has been a focus of intensive research. Notably, whereas thousands of genes contain a CRE, the functional regulation of gene expression by the CRE:CREB system is limited to ∼100 genes, and likely requires additional proteins. Here, we investigated the role of a member of the CREB complex, CREB binding protein (CBP), in basal and stress-induced CRH expression during development and in the adult. Using mice with a deficient CREB-binding site on CBP, we found that CBP:CREB interaction is necessary for normal basal CRH expression at the mRNA and protein level in the nine-day-old mouse, prior to onset of functional regulation of hypothalamic CRH expression by glucocorticoids. This interaction, which functions directly on crh or indirectly via regulation of other genes, was no longer required for maintenance of basal CRH expression levels in the adult. However, CBP:CREB binding contributed to stress-induced CRH expression in the adult, enabling rapid CRH synthesis in hypothalamus. CBP:CREB binding deficiency did not disrupt basal corticosterone plasma levels or acute stress-evoked corticosterone release. Because dysregulation of CRH expression occurs in stress-related disorders including depression, a full understanding of the complex regulation of this gene is important in both health and disease.
Highlights
Basal corticotropin-releasing hormone (CRH) expression levels in paraventricular nucleus (PVN) are reduced by CREB binding protein (CBP):cAMP response element-binding protein (CREB) binding deficiency on postnatal day 9
There was a tendency towards a gene dose effect on CRH mRNA expression because CRH mRNA expression in heterozygous (CbpKIX/+) mice was intermediate between levels in wild-type and CbpKIX/KIX mice
These findings suggested that CBP:CREB interaction contributed to basal mRNA CRH expression in the PVN of the developing rodent
Summary
The neuropeptide corticotropin-releasing hormone (CRH) coordinates neuroendocrine, autonomic and behavioral responses to stress (Aguilera, 2011; Bale & Vale, 2004; Bonfiglio et al, 2011; Brunson et al, 2001a; Coste et al, 2001; de Kloet et al, 2005; Herman et al, 2003; Joëls & Baram, 2009; Lightman, 2008; Valentino & Van Bockstaele, 2008; Zoumakis & Chrousos, 2010), and dysfunctional CRH regulation is present in several stress-related affective disorders including anxiety and major depression (de Kloet et al, 2005; Flandreau et al, 2012; Lloyd & Nemeroff, 2011; Sink et al, 2012). The crh promoter contains an important, functional cyclic AMP response element (CRE) (Seasholtz et al, 1988; Spengler et al, 1992) that is activated by cyclic adenosine 3′, 5′ monophosphate (cAMP) stimulation (Itoi et al, 1998; Seasholtz et al, 1988; Spengler et al, 1992) and is required for stress-induced crh transcriptional activation in the hypothalamus in both mature (Itoi et al, 1998; Liu & Aguilera, 2009) and developing (Chen et al, 2001; Hatalski & Baram, 1997) brain. There is little information about the role of CBP in enabling CREB-mediated regulation of crh expression
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