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Association of Gnrhr mRNA With the Stem Cell Determinant Musashi: A Mechanism for Leptin-Mediated Modulation of GnRHR Expression.
- Source :
-
Endocrinology [Endocrinology] 2018 Feb 01; Vol. 159 (2), pp. 883-894. - Publication Year :
- 2018
-
Abstract
- The cyclic expression of pituitary gonadotropin-releasing hormone receptors (GnRHRs) may be an important checkpoint for leptin regulatory signals. Gonadotrope Lepr-null mice have reduced GnRHR levels, suggesting these receptors may be leptin targets. To determine if leptin stimulated GnRHR directly, primary pituitary cultures or pieces were exposed to 1 to 100 nM leptin. Leptin increased GnRHR protein levels and the percentages of gonadotropes that bound biotinylated analogs of gonadotropin-releasing hormone (bio-GnRH) but had no effect on Gnrhr messenger RNA (mRNA). An in silico analysis revealed three consensus Musashi (MSI) binding elements (MBEs) for this translational control protein in the 3' untranslated region (UTR) of Gnrhr mRNA. Several experiments determined that these Gnrhr mRNA MBE were active: (1) RNA electrophoretic mobility shift assay analyses showed that MSI1 specifically bound Gnrhr mRNA 3'-UTR; (2) RNA immunoprecipitation of pituitary fractions with MSI1 antibody pulled down a complex enriched in endogenous MSI protein and endogenous Gnrhr mRNA; and (3) fluorescence reporter assays showed that MSI1 repressed translation of the reporter coupled to the Gnrhr 3'-UTR. In vitro, leptin stimulation of pituitary pieces reduced Msi1 mRNA in female pituitaries, and leptin stimulation of pituitary cultures reduced MSI1 proteins selectively in gonadotropes identified by binding to bio-GnRH. These findings show that leptin's direct stimulatory actions on gonadotrope GnRHR correlate with a direct inhibition of expression of the posttranscriptional regulator MSI1. We also show MSI1 interaction with the 3'-UTR of Gnrhr mRNA. These findings now open the door to future studies of leptin-modulated posttranscriptional pathways.<br /> (Copyright © 2018 Endocrine Society.)
- Subjects :
- Animals
Cell Lineage drug effects
Cell Lineage genetics
Cells, Cultured
Female
Gene Expression Regulation drug effects
Gonadotrophs drug effects
Gonadotrophs metabolism
Male
Mice
Mice, Knockout
Promoter Regions, Genetic drug effects
RNA, Messenger metabolism
Receptors, LHRH metabolism
Leptin pharmacology
Nerve Tissue Proteins metabolism
RNA-Binding Proteins metabolism
Receptors, LHRH genetics
Stem Cells metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1945-7170
- Volume :
- 159
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Endocrinology
- Publication Type :
- Academic Journal
- Accession number :
- 29228137
- Full Text :
- https://doi.org/10.1210/en.2017-00586