Abstract
Gonadotropin-releasing hormone (GnRH) and activin regulate synthesis of FSH and ultimately fertility. Recent in vivo studies cast SMAD4 and FOXL2 as master transcriptional mediators of activin signaling that act together and independently of GnRH to regulate Fshb gene expression and female fertility. Ovarian hormones regulate GnRH and its receptor (GNRHR) through negative and positive feedback loops. In contrast, the role of ovarian hormones in regulating activin, activin receptors, and components of the activin signaling pathway, including SMAD4 and FOXL2, remains understudied. The widespread distribution of activin and many of its signaling intermediates complicates analysis of the effects of ovarian hormones on their synthesis in gonadotropes, one of five pituitary cell types. We circumvented this complication by using a transgenic model that allows isolation of polyribosomes selectively from gonadotropes of intact females and ovariectomized females treated with or without a GnRH antagonist. This paradigm allows assessment of ovarian hormonal feedback and distinguishes responses that are either independent or dependent on GnRH. Surprisingly, our results indicate that Foxl2 levels in gonadotropes decline significantly in the absence of ovarian input and independently of GnRH. Expression of the genes encoding other members of the activin signaling pathway are unaffected by loss of ovarian hormonal feedback, highlighting their selective effect on Foxl2. Expression of Gnrhr, a known target of FOXL2, also declines upon ovariectomy consistent with reduced expression of Foxl2 and loss of ovarian hormones. In contrast, Fshb mRNA increases dramatically post-ovariectomy due to increased compensatory input from GnRH. Together these data suggest that ovarian hormones regulate expression of Foxl2 thereby expanding the number of genes controlled by the hypothalamic-pituitary-gonadal axis that ultimately dictate reproductive fitness.
Highlights
Reproductive fitness requires tight regulation of the genes encoding LH and FSH
Results from the Gonadotrope specific RiboTag (GRT) mice indicate that OVX has a minimal impact on the levels of activin and inhibin subunit mRNAs in total pituitary extracts, with the exception of Inhbb mRNA increasing by two-fold after OVX (Fig 4A, 4B and 4C)
Our results suggest that even though activin and inhibin are important regulators of Fshb expression [2, 3, 12], their subunit mRNA levels in the gonadotrope appear to be independent of the ovary and refractory to the changes in Gonadotropin-releasing hormone (GnRH) that occur with the OVX/ Antide paradigm
Summary
A complex network of signals emanate from the hypothalamic-pituitary-gonadal axis defining a characteristic temporal pattern of synthesis and secretion of LH and FSH that occurs over the course of the estrous cycle in rodents [1,2,3]. Peaks of LH and FSH that occur during late proestrus trigger ovulation [4]. This combined surge reflects primarily an increase in frequency and amplitude of pulses of GnRH from the hypothalamus [5,6,7]. Additional contributions from hypothalamic kisspeptin, pituitary adenylate cyclase-activating polypeptide, and pituitary bone morphogenetic proteins, as well as steroid feedback from the gonads, further define the frequency and amplitude of the preovulatory surge of LH and FSH [2, 8, 9]
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