Sex-Dependent Mechanisms of Glucocorticoid Regulation of the Mouse Hypothalamic Corticotropin-Releasing Hormone Gene
| Autor: | Maranda K. Thompson, Ashley L Heck, Rosalie M. Uht, Robert J. Handa |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty endocrine system Corticotropin-Releasing Hormone Hypothalamus Estrous Cycle Mice Inbred Strains Biology Gonadotropin-Releasing Hormone 03 medical and health sciences Mice 0302 clinical medicine Endocrinology Glucocorticoid receptor Sex Factors Internal medicine Coactivator medicine Animals Androstanols RNA Messenger Receptor Glucocorticoids Estrous cycle Neurons Estradiol Adrenalectomy CRTC2 030104 developmental biology Glucocorticoid secretion nervous system Gene Expression Regulation Vagina Female 030217 neurology & neurosurgery Glucocorticoid hormones hormone substitutes and hormone antagonists Hormone medicine.drug Research Article |
| Zdroj: | Endocrinology |
| ISSN: | 1945-7170 |
| Popis: | To limit excessive glucocorticoid secretion following hypothalamic-pituitary-adrenal (HPA) axis stimulation, circulating glucocorticoids inhibit corticotropin-releasing hormone (CRH) expression in paraventricular nucleus (PVN) neurons. As HPA function differs between sexes and depends on circulating estradiol (E2) levels in females, we investigated sex/estrous stage-dependent glucocorticoid regulation of PVN Crh. Using NanoString nCounter technology, we first demonstrated that adrenalectomized (ADX’d) diestrous female (low E2), but not male or proestrous female (high E2), mice exhibited a robust decrease in PVN CRH mRNA following 2-day treatment with the glucocorticoid receptor (GR) agonist RU28362. Immunohistochemical analysis of PVN CRH neurons in Crh-IRES-Cre;Ai14 mice, where TdTomato fluorescence permanently tags CRH-expressing neurons, showed similarly abundant co-expression of GR-immunoreactivity in males, diestrous females, and proestrous females. However, we identified sex/estrous stage-related glucocorticoid regulation or expression of GR transcriptional coregulators. Out of 17 coregulator genes examined using nCounter multiplex analysis, mRNAs that were decreased by RU28362 in ADX’d mice in a sex/estrous stage-dependent fashion included: GR (males = diestrous females > proestrous females), signal transducer and activator of transcription 3 (STAT3) (males < diestrous = proestrous), and HDAC1 (males < diestrous > proestrous). Steroid receptor coactivator 3 (SRC-3), nuclear corepressor 1 (NCoR1), heterogeneous nuclear ribonucleoprotein U (hnrnpu), CREB binding protein (CBP) and CREB-regulated transcription coactivator 2 (CRTC2) mRNAs were lower in ADX’d diestrous and proestrous females versus males. Additionally, most PVN CRH neurons co-expressed methylated CpG binding protein 2 (MeCP2)-immunoreactivity in diestrous female and male Crh-IRES-Cre;Ai14 mice. Our findings collectively suggest that GR’s sex-dependent regulation of PVN Crh may depend upon differences in the GR transcriptional machinery and an underlying influence of E2 levels in females. |
| Databáze: | OpenAIRE |
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