Identification of SPRED2 (sprouty-related protein with EVH1 domain 2) as a negative regulator of the hypothalamic-pituitary-adrenal axis.
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Identification of SPRED2 (sprouty-related protein with EVH1 domain 2) as a negative regulator of the hypothalamic-pituitary-adrenal axis. / Ullrich, Melanie; Bundschu, Karin; Benz, Peter M; Abesser, Marco; Freudinger, Ruth; Fischer, Tobias; Ullrich, Julia; Renné, Thomas; Walter, Ulrich; Schuh, Kai.
in: J BIOL CHEM, Jahrgang 286, Nr. 11, 11, 2011, S. 9477-9488.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Identification of SPRED2 (sprouty-related protein with EVH1 domain 2) as a negative regulator of the hypothalamic-pituitary-adrenal axis.
AU - Ullrich, Melanie
AU - Bundschu, Karin
AU - Benz, Peter M
AU - Abesser, Marco
AU - Freudinger, Ruth
AU - Fischer, Tobias
AU - Ullrich, Julia
AU - Renné, Thomas
AU - Walter, Ulrich
AU - Schuh, Kai
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Animals
KW - Mice
KW - Mice, Knockout
KW - Nerve Tissue Proteins/genetics/metabolism
KW - Repressor Proteins/genetics/metabolism
KW - Hypothalamus/metabolism
KW - Extracellular Signal-Regulated MAP Kinases/genetics/metabolism
KW - Phosphorylation/physiology
KW - Corticotropin-Releasing Hormone/genetics/secretion
KW - Hypothalamo-Hypophyseal System/metabolism
KW - Pituitary-Adrenal System/metabolism
KW - Animals
KW - Mice
KW - Mice, Knockout
KW - Nerve Tissue Proteins/genetics/metabolism
KW - Repressor Proteins/genetics/metabolism
KW - Hypothalamus/metabolism
KW - Extracellular Signal-Regulated MAP Kinases/genetics/metabolism
KW - Phosphorylation/physiology
KW - Corticotropin-Releasing Hormone/genetics/secretion
KW - Hypothalamo-Hypophyseal System/metabolism
KW - Pituitary-Adrenal System/metabolism
M3 - SCORING: Journal article
VL - 286
SP - 9477
EP - 9488
JO - J BIOL CHEM
JF - J BIOL CHEM
SN - 0021-9258
IS - 11
M1 - 11
ER -
