Expression profiling identifies the CRH/CRH-R1 system as a modulator of neurovascular gene activity
Expression profiling identifies the CRH/CRH-R1 system as a modulator of neurovascular gene activity
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DOI：
10.1038/sj.jcbfm.9600451
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发表时间：
2007-08-01
影响因子：
6.3
通讯作者：
Wurst, Wolfgang
中科院分区：
文献类型：
--
作者：
Deussing, Jan M.;Kuehne, Claudia;Wurst, Wolfgang
促肾上腺皮质激素释放激素受体1型（CRH-R1）缺陷小鼠表现出焦虑样行为减少，慢性皮质酮缺乏，以及由下丘脑-垂体-肾上腺皮质（HPA）轴破坏引起的神经内分泌应激反应受损。CRH/CRH-R1依赖性信号传导机制的分子底物和途径是行为表型的基础，以及终身糖皮质激素缺乏的后果仍然很不清楚。为了解剖涉及的神经元回路，我们使用我们定制的MPIP（Max Planck Institute of Psychiatry）17 k cDNA微阵列对CRH-R1突变体和野生型小鼠的脑进行比较表达谱分析。微阵列分析产生了107个基因，当将CRH-R1敲除小鼠与野生型同窝仔比较时，这些基因显示出改变的表达水平。一个显着比例的差异表达基因相关的HPA和下丘脑垂体-甲状腺（HPT）轴的控制，反映不仅在CRH-R1突变小鼠HPA轴的干扰，但也相互作用的神经内分泌系统。调控基因的空间分析揭示了在脑微血管中表达的基因的流行。这种表型通过CRH过表达小鼠中调节基因的成功交叉验证得到了证实。CRH-R1突变和CRH过表达小鼠的脑血管分析显示功能而不是结构特性的改变。CRH/CRH-R1系统的直接作用通过证明Crhr 1在成年小鼠脑血管中的表达得到支持。总之，这些数据表明，一种新的，以前未知的CRH/CRH-R1系统在调节神经血管基因的表达和功能的作用。
Corticotropin-releasing hormone receptor type 1 (CRH-R1)-deficient mice display reduced anxiety-like behavior, a chronic corticosterone deficit, and an impaired neuroendocrine stress response caused by disruption of the hypothalamic-pituitary-adrenocortical (HPA) axis. The molecular substrates and pathways of CRH/CRH-R1-dependent signaling mechanisms underlying the behavioral phenotype as well as the consequences of lifelong glucocorticoid deficit remain largely obscure. To dissect involved neuronal circuitries, we performed comparative expression profiling of brains of CRH-R1 mutant and wild-type mice using our custom made MPIP (Max Planck Institute of Psychiatry) 17k cDNA microarray. Microarray analysis yielded 107 genes showing altered expression levels when comparing CRH-R1 knockout mice with wild-type littermates. A significant proportion of differentially expressed genes was related to control of HPA and hypothalamic pituitary-thyroid (HPT) axes reflecting not only the disturbance of the HPA axis in CRH-R1 mutant mice but also the interplay of both neuroendocrine systems. The spatial analysis of regulated genes revealed a prevalence for genes expressed in the cerebral microvasculature. This phenotype was confirmed by the successful cross-validation of regulated genes in CRH overexpressing mice. Analysis of the cerebral vasculature of CRH-R1 mutant and CRH overexpressing mice revealed alterations of functional rather than structural properties. A direct role of the CRH/CRH-R1 system was supported by demonstrating Crhr1 expression in the adult murine cerebral vasculature. In conclusion, these data suggest a novel, previously unknown role of the CRH/CRH-R1 system in modulating neurovascular gene expression and function.