title: Identification of SPRED2 (sprouty-related protein with EVH1 domain 2) as a negative regulator of the hypothalamic-pituitary-adrenal axis.
abstract: Sprouty-related proteins with EVH1 (enabled/vasodilator-stimulated phosphoprotein homology 1) domain (SPREDs) are inhibitors of MAPK signaling. To elucidate SPRED2 in vivo function, we characterized body homeostasis in SPRED2(-/-) mice. They showed a doubled daily water uptake, induced by elevated serum osmolality, originating from increased blood salt load. Accordingly, serum aldosterone was doubled, accompanied by augmented adrenal aldosterone synthase (AS) expression. Surprisingly, serum vasopressin (AVP) was unaltered, and, as evidenced by halved angiotensin II (Ang II) levels, the renin angiotensin system (RAS) was down-regulated. Adrenocorticotropic hormone (ACTH) was significantly elevated in SPRED2(-/-) mice, together with its secretagogue corticotropin-releasing hormone (CRH) and its downstream target corticosterone. ERK phosphorylation in brains was augmented, and hypothalamic CRH mRNA levels were elevated, both contributing to the increased CRH release. Our data were supported by CRH promoter reporter assays in hypothalamic mHypoE-44 cells, revealing a SPRED-dependent inhibition of Ets (ERK/E-twenty-six)-dependent transcription. Furthermore, SPRED suppressed CRH production in these cells. In conclusion, our study suggests that SPRED2 deficiency leads to an increased MAPK signaling, which results in an augmented CRH promoter activity. The subsequent CRH overproduction causes an up-regulation of downstream hypothalamic-pituitary-adrenal (HPA) hormone secretion. This constitutes a possible trigger for the observed compulsive grooming in SPRED2(-/-) mice and may, together with hyperplasia of aldosterone-producing cells, contribute to the hyperaldosteronism and homeostatic imbalances.
authors.affiliation: Institute of Physiology I, University of Wuerzburg, Roentgenring 9, 97070 Wuerzburg, Germany. m.ullrich@uni-wuerzburg.de
authors.forename: Melanie
authors.initials: M
authors.lastname: Ullrich
authors.forename: Karin
authors.initials: K
authors.lastname: Bundschu
authors.forename: Peter M
authors.initials: PM
authors.lastname: Benz
authors.forename: Marco
authors.initials: M
authors.lastname: Abesser
authors.forename: Ruth
authors.initials: R
authors.lastname: Freudinger
authors.forename: Tobias
authors.initials: T
authors.lastname: Fischer
authors.forename: Julia
authors.initials: J
authors.lastname: Ullrich
authors.forename: Thomas
authors.initials: T
authors.lastname: Renné
authors.forename: Ulrich
authors.initials: U
authors.lastname: Walter
authors.forename: Kai
authors.initials: K
authors.lastname: Schuh
mesh_terms: D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; C433764:Spred2 protein, mouse; D003346:Corticotropin-Releasing Hormone; D048049:Extracellular Signal-Regulated MAP Kinases