Urocortin expression in the Edinger-Westphal nucleus is up-regulated by stress and corticotropin-releasing hormone deficiency

Urocortin is a 40-amino acid mammalian peptide related to CRH and urotensin . The physiological role of urocortin is unknown, but it has been postulate d to serve some of the functions previously attributed to CRH. We had earli er found that urocortin messenger RNA (mRNA) expression within the mouse br ain is confined to the region of the Edinger-Westphal (EW) nucleus of the m idbrain. To further characterize the regulation of the urocortin gene, we f irst cloned and sequenced the mouse gene, confirming the presence of a sing le gene in the murine genome. A general survey of mouse tissues using North ern blot analysis revealed the presence of urocortin mRNA only within the m idbrain. By in situ hybridization analysis, we found that urocortin mRNA ex pression in the EW nucleus is responsive to stress, as mRNA levels increase d approximately 3-fold after 3 h of restraint. Chronic glucocorticoid treat ment, although not affecting basal levels, blocked the stress-induced rise in urocortin mRNA. Using CRH-deficient [knockout (KO)] mice, we examined th e effect of combined CRH and glucocorticoid deficiency upon urocortin mRNA expression. As in wild-type (WT) mice, we had previously found that urocort in expression in CRHKO mouse brain was not detected outside of the EW nucle us. However, we found that urocortin expression within the EW of CRHKO mice is up-regulated 2- to 3-fold compared with that in WT mice. This up-regula tion is not due to a lack of inhibition by glucocorticoids, as urocortin mR NA levels in the EW nucleus of CRHKO mice did not change after glucocortico id supplementation. As the EW does not project to any brain regions known t o be involved in the behavioral responses to stress, urocortin expressed in this site is unlikely to mediate stress-induced behaviors. On the other ha nd, as the EW nucleus may play a role in the regulation of the autonomic ne rvous system and projects to various brain stem nuclei that express the CRH receptor, urocortin originating in the EW may play a role in the regulatio n of the autonomic nervous system during stress.