Expression Profiling Identifies the CRH/CRH-R1 System as a Modulator of Neurovascular Gene Activity

Abstract

Corticotropin-releasing hormone receptor type 1 (CRH-R1)-deficient mice display reduced anxietylike 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 hypothalamicpituitary-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.

Gene Expression Studies in Major Depression

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An Islet-Targeted Genome-Wide Association Scan Identifies Novel Genes Implicated in Cytokine-Mediated Islet Stress in Type 2 Diabetes

“…GWAS studies have repeatedly shown that polymorphisms related to ␤-cell function and/or development are closely associated with type 2 diabetes (16,17), reviewed in (18). For this study, the acute insulin response to glucose (AIRg) test from the GUARDIAN Consortium was used as an indicator of islet function to evaluate genes from the rodent microarray (13).…”

Urocortin 3 Modulates Social Discrimination Abilities via Corticotropin-Releasing Hormone Receptor Type 2

“…All sections were processed for in situ hybridization as previously described (Deussing et al, 2007). The riboprobe for UCN3 covered nucleotides 505-1136 of GenBank accession number NM_031250 and was generated by PCR, labeled, and hybridized as previously described (Deussing et al, 2007). The hybridized slides were dipped in autoradiographic emulsion (type NTB2; Eastman Kodak), developed after 3-6 weeks, and counterstained with cresyl violet.…”

“…This procedure allowed for parallel in situ hybridization of sections under identical conditions assuring meaningful quantification and comparison of hybridization signals. All sections were processed for in situ hybridization as previously described (Deussing et al, 2007). The riboprobe for UCN3 covered nucleotides 505-1136 of GenBank accession number NM_031250 and was generated by PCR, labeled, and hybridized as previously described (Deussing et al, 2007).…”