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Urocortin Expression in the Edinger-Westphal Nucleus Is Up-Regulated by Stress and Corticotropin-Releasing Hormone Deficiency¹

Program in Neuroscience, Howard Hughes Medical Institute, Harvard Medical School (S.C.W.), and the Division of Endocrinology, Children’s Hospital, Harvard Medical School (S.C.W., J.A.M.), Boston, Massachusetts 02115; and The Jackson Laboratory (L.L.P.), Bar Harbor, Maine 04609

Address all correspondence and requests for reprints to: Dr. J. A. Majzoub, Division of Endocrinology, Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115. E-mail: majzoub{at}a1.tch.harvard.edu

Urocortin is a 40-amino acid mammalian peptide related to CRH and urotensin. The physiological role of urocortin is unknown, but it has been postulated to serve some of the functions previously attributed to CRH. We had earlier found that urocortin messenger RNA (mRNA) expression within the mouse brain is confined to the region of the Edinger-Westphal (EW) nucleus of the midbrain. To further characterize the regulation of the urocortin gene, we first cloned and sequenced the mouse gene, confirming the presence of a single gene in the murine genome. A general survey of mouse tissues using Northern blot analysis revealed the presence of urocortin mRNA only within the midbrain. By in situ hybridization analysis, we found that urocortin mRNA expression in the EW nucleus is responsive to stress, as mRNA levels increased approximately 3-fold after 3 h of restraint. Chronic glucocorticoid treatment, although not affecting basal levels, blocked the stress-induced rise in urocortin mRNA. Using CRH-deficient [knockout (KO)] mice, we examined the effect of combined CRH and glucocorticoid deficiency upon urocortin mRNA expression. As in wild-type (WT) mice, we had previously found that urocortin expression in CRHKO mouse brain was not detected outside of the EW nucleus. 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-regulation is not due to a lack of inhibition by glucocorticoids, as urocortin mRNA levels in the EW nucleus of CRHKO mice did not change after glucocorticoid supplementation. As the EW does not project to any brain regions known to be involved in the behavioral responses to stress, urocortin expressed in this site is unlikely to mediate stress-induced behaviors. On the other hand, as the EW nucleus may play a role in the regulation of the autonomic nervous system and projects to various brain stem nuclei that express the CRH receptor, urocortin originating in the EW may play a role in the regulation of the autonomic nervous system during stress.

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