Differential contribution of CBP:CREB binding to corticotropin-releasing hormone expression in the infant and adult hypothalamus
Differential contribution of CBP:CREB binding to corticotropin-releasing hormone expression in the infant and adult hypothalamus
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DOI：
10.3109/10253890.2013.806907
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发表时间：
2014-01-01
影响因子：
2.3
通讯作者：
Baram, Tallie Z.
中科院分区：
文献类型：
--
作者：
Cope, Jessica L.;Regev, Limor;Baram, Tallie Z.
促肾上腺皮质激素释放激素（CRH）对中枢和外周应激反应的调节起着至关重要的作用。由于精细调节应激系统的重要性，CRH表达以器官和脑区域特异性方式受到严格调节。因此，在下丘脑中，CRH是组成性表达的，并且这种表达通过应激进一步增强;然而，其潜在的调节机制尚未完全了解。crh基因的调控区包含几个元件，包括环AMP反应元件（CRE），并且CRE与环AMP反应元件结合蛋白（CREB）的相互作用在CRH表达中的作用一直是深入研究的焦点。值得注意的是，尽管数千个基因含有CRE，但CRE：CREB系统对基因表达的功能性调节仅限于100个基因，并且可能需要额外的蛋白质。在这里，我们调查的CREB复合物，CREB结合蛋白（CBP）的成员，在基础和应力诱导的CRH表达在发展过程中和成人的作用。使用CBP上CREB结合位点缺陷的小鼠，我们发现CBP：CREB相互作用对于9天龄小鼠在mRNA和蛋白水平上的正常基础CRH表达是必要的，在糖皮质激素对下丘脑CRH表达的功能调节开始之前。这种相互作用直接作用于CRH或间接通过调节其他基因，不再需要维持成人的基础CRH表达水平。然而，CBP：CREB结合有助于应激诱导的CRH表达在成人中，使快速CRH合成在下丘脑。CBP：CREB结合缺陷不会破坏基础皮质酮血浆水平或急性应激诱发的皮质酮释放。由于CRH表达失调发生在与压力相关的疾病中，包括抑郁症，因此充分了解该基因的复杂调控对健康和疾病都很重要。
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 similar 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.