Adrenal and Ovarian Phenotype of a Tissue-Specific Urocortin 2-Overexpressing Mouse Model.
Urocortin 2 (UCN2) is a neuropeptide of the CRH family, involved in homeostatic mechanisms, the stress response, and control of anxiety. To elucidate the effects of UCN2 on steroidogenesis, we developed a mouse model that allows a Cre recombinase-determined conditional overexpression of UCN2 (UCN2-COE). In these mice SF1-Cre-driven overexpression of UCN2 was restricted to the adrenal glands, gonads, and parts of the hypothalamus. UCN2-COE animals of both sexes revealed significantly higher plasma UCN2 levels and significantly higher UCN2 expression levels in the adrenals and ovaries. In contrast, the baseline expression of UCN2 was already high in the testes of control mice with no further increase achievable in UCN2-COE animals. Adrenal steroidogenesis of UCN2-COE animals was investigated under baseline conditions, upon an ACTH stimulation test, and following a restraint stress test. A tendency toward lower expression of steroidogenic enzymes was detectable in UCN2-COE animals of both sexes with slight differences between males and females. A similar reduction in the expression levels of the final steps of ovarian steroidogenesis, accompanied by reduced plasma estradiol levels, was observed in female UCN2-COE animals. Thus, adrenal UCN2 overexpression resulted in down-regulation of adrenal steroidogenesis, suggesting a reduction in the stress response in the mouse (stress coping behavior). Similarly, UCN2 overexpression in the ovaries caused a decrease in steroidogenesis and reduction of follicles that had undergone ovulation. Nevertheless, this finding was not associated with reduced fertility.
Endocrine Research Unit (A.S., A.R., K.M.-P., C.H., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, D-80336 Munich, Germany; Department Stress Neurobiology and Neurogenetics (A.L., J.R., C.K., J.M.D.), Max Planck Institute of Psychiatry, D-80804 Munich, Germany; and Division of Pediatric Endocrinology and Diabetes (A.K., F.R.), Department of Pediatrics, University Hospital Schleswig-Holstein, Christian Albrechts University Kiel, D-24105 Kiel, Germany.
Ariadni
A
Spyroglou
Endocrine Research Unit (A.S., A.R., K.M.-P., C.H., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, D-80336 Munich, Germany; Department Stress Neurobiology and Neurogenetics (A.L., J.R., C.K., J.M.D.), Max Planck Institute of Psychiatry, D-80804 Munich, Germany; and Division of Pediatric Endocrinology and Diabetes (A.K., F.R.), Department of Pediatrics, University Hospital Schleswig-Holstein, Christian Albrechts University Kiel, D-24105 Kiel, Germany.
Anna
A
Riester
Endocrine Research Unit (A.S., A.R., K.M.-P., C.H., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, D-80336 Munich, Germany; Department Stress Neurobiology and Neurogenetics (A.L., J.R., C.K., J.M.D.), Max Planck Institute of Psychiatry, D-80804 Munich, Germany; and Division of Pediatric Endocrinology and Diabetes (A.K., F.R.), Department of Pediatrics, University Hospital Schleswig-Holstein, Christian Albrechts University Kiel, D-24105 Kiel, Germany.
Katharina
K
Mueller-Peltzer
Endocrine Research Unit (A.S., A.R., K.M.-P., C.H., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, D-80336 Munich, Germany; Department Stress Neurobiology and Neurogenetics (A.L., J.R., C.K., J.M.D.), Max Planck Institute of Psychiatry, D-80804 Munich, Germany; and Division of Pediatric Endocrinology and Diabetes (A.K., F.R.), Department of Pediatrics, University Hospital Schleswig-Holstein, Christian Albrechts University Kiel, D-24105 Kiel, Germany.
Ailing
A
Lu
Endocrine Research Unit (A.S., A.R., K.M.-P., C.H., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, D-80336 Munich, Germany; Department Stress Neurobiology and Neurogenetics (A.L., J.R., C.K., J.M.D.), Max Planck Institute of Psychiatry, D-80804 Munich, Germany; and Division of Pediatric Endocrinology and Diabetes (A.K., F.R.), Department of Pediatrics, University Hospital Schleswig-Holstein, Christian Albrechts University Kiel, D-24105 Kiel, Germany.
Juliane
J
Rohde
Endocrine Research Unit (A.S., A.R., K.M.-P., C.H., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, D-80336 Munich, Germany; Department Stress Neurobiology and Neurogenetics (A.L., J.R., C.K., J.M.D.), Max Planck Institute of Psychiatry, D-80804 Munich, Germany; and Division of Pediatric Endocrinology and Diabetes (A.K., F.R.), Department of Pediatrics, University Hospital Schleswig-Holstein, Christian Albrechts University Kiel, D-24105 Kiel, Germany.
Constanze
C
Hantel
Endocrine Research Unit (A.S., A.R., K.M.-P., C.H., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, D-80336 Munich, Germany; Department Stress Neurobiology and Neurogenetics (A.L., J.R., C.K., J.M.D.), Max Planck Institute of Psychiatry, D-80804 Munich, Germany; and Division of Pediatric Endocrinology and Diabetes (A.K., F.R.), Department of Pediatrics, University Hospital Schleswig-Holstein, Christian Albrechts University Kiel, D-24105 Kiel, Germany.
Claudia
C
Kuehne
Endocrine Research Unit (A.S., A.R., K.M.-P., C.H., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, D-80336 Munich, Germany; Department Stress Neurobiology and Neurogenetics (A.L., J.R., C.K., J.M.D.), Max Planck Institute of Psychiatry, D-80804 Munich, Germany; and Division of Pediatric Endocrinology and Diabetes (A.K., F.R.), Department of Pediatrics, University Hospital Schleswig-Holstein, Christian Albrechts University Kiel, D-24105 Kiel, Germany.
Alexandra
A
Kulle
Endocrine Research Unit (A.S., A.R., K.M.-P., C.H., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, D-80336 Munich, Germany; Department Stress Neurobiology and Neurogenetics (A.L., J.R., C.K., J.M.D.), Max Planck Institute of Psychiatry, D-80804 Munich, Germany; and Division of Pediatric Endocrinology and Diabetes (A.K., F.R.), Department of Pediatrics, University Hospital Schleswig-Holstein, Christian Albrechts University Kiel, D-24105 Kiel, Germany.
Felix
F
Riepe
Endocrine Research Unit (A.S., A.R., K.M.-P., C.H., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, D-80336 Munich, Germany; Department Stress Neurobiology and Neurogenetics (A.L., J.R., C.K., J.M.D.), Max Planck Institute of Psychiatry, D-80804 Munich, Germany; and Division of Pediatric Endocrinology and Diabetes (A.K., F.R.), Department of Pediatrics, University Hospital Schleswig-Holstein, Christian Albrechts University Kiel, D-24105 Kiel, Germany.
Jan M
JM
Deussing
Endocrine Research Unit (A.S., A.R., K.M.-P., C.H., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, D-80336 Munich, Germany; Department Stress Neurobiology and Neurogenetics (A.L., J.R., C.K., J.M.D.), Max Planck Institute of Psychiatry, D-80804 Munich, Germany; and Division of Pediatric Endocrinology and Diabetes (A.K., F.R.), Department of Pediatrics, University Hospital Schleswig-Holstein, Christian Albrechts University Kiel, D-24105 Kiel, Germany.
Felix
F
Beuschlein
D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics; D006907:17-alpha-Hydroxypregnenolone / Q000378:metabolism; D015096:3-Hydroxysteroid Dehydrogenases / Q000187:drug effects / Q000235:genetics; D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000187:drug effects / Q000235:genetics; D003346:Corticotropin-Releasing Hormone / Q000235:genetics*; D019405:Cytochrome P-450 CYP11B2 / Q000187:drug effects / Q000235:genetics; D004958:Estradiol / Q000378:metabolism; D005260:Female; D055879:Gene Knock-In Techniques; D012739:Gonadal Steroid Hormones; D008297:Male; D051379:Mice; D010053:Ovary / Q000033:anatomy & histology / Q000378:metabolism*; D010641:Phenotype; D010750:Phosphoproteins / Q000187:drug effects / Q000235:genetics; D011374:Progesterone / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013252:Steroid 11-beta-Hydroxylase / Q000187:drug effects / Q000235:genetics; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics; D013737:Testis / Q000378:metabolism; D054832:Urocortins / Q000235:genetics*; D000098682:Steroidogenic Acute Regulatory Protein
D012739:Gonadal Steroid Hormones; D010750:Phosphoproteins; D012333:RNA, Messenger; D054832:Urocortins; D000098682:Steroidogenic Acute Regulatory Protein; C518358:urocortin 2, mouse; D006907:17-alpha-Hydroxypregnenolone; D011374:Progesterone; D004958:Estradiol; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D015067:17-Hydroxysteroid Dehydrogenases; D015096:3-Hydroxysteroid Dehydrogenases; C576264:hydroxysteroid (17-beta) dehydrogenase 1, mouse; D001141:Aromatase; D013254:Steroid 17-alpha-Hydroxylase; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme