Expression profiling identifies the CRH/CRH-R1 system as a modulator of neurovascular gene activity.
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.
Deussing
Jan M
JM
Max Planck Institute of Psychiatry, Munich, Germany. deussing@mpipsykl.mpg.de
Kühne
Claudia
C
Pütz
Benno
B
Panhuysen
Markus
M
Breu
Johannes
J
Stenzel-Poore
Mary P
MP
Holsboer
Florian
F
Wurst
Wolfgang
W
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000098:blood supply* / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000502:physiology; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D010913:Pituitary-Adrenal System / Q000502:physiology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000502:physiology; D000099052:CRF Receptor, Type 1
C101531:CRF receptor type 2; D005938:Glucocorticoids; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D000469:Alkaline Phosphatase