Maximal Expression of Foxl2 in Pituitary Gonadotropes Requires Ovarian Hormones

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.

Identification and analysis of differentially expressed long non-coding RNAs between multiparous and uniparous goat (Capra hircus) ovaries

“…In addition, Neat1 knockout mice fail to become pregnant despite normal ovulation [ 49 ]. Ovarian hormones can regulate the expression of Foxl2 to expand the number of genes controlled by the hypothalamic–pituitary–gonadal axis, ultimately dictating reproductive fitness [ 16 ].…”

“…Boulanger promised that Forkhead box L2 ( Foxl2 ) loss of function dissociated from loss of lncRNA expression is sufficient to cause an XX female-to-male sex reversal in the goat model and, as in the mouse model, an agenesis of eyelids [ 15 ]. Ovarian hormones regulate Foxl2 expression and thereby expand the number of genes controlled by the hypothalamic–pituitary–gonad axis that ultimately dictates reproductive fitness [ 16 ]. Although lncRNA studies have been begun in several species, the research conducted into the effects of lncRNA on the reproductive rate was relatively limited.…”

Role of mRNAs and long non‐coding RNAs in regulating the litter size trait in Chuanzhong black goats

“…In addition, Nakagawa et al () reported that Neat1 knock‐out mice failed to conceive despite normal ovulation. Ovarian hormones can regulate Foxl2 expression to increase the number of genes controlled by the hypothalamic–pituitary–gonadal axis, eventually dictating reproductive fitness (Herndon & Nilson, ).…”

Single Nucleotide Polymorphisms in the HIRA Gene Affect Litter Size in Small Tail Han Sheep

“…The HIRA expression in ovary, oviduct and uterus of low fecundity Sunite sheep was higher than those in high fecundity Small Tail Han sheep indicated that the expression of HIRA may negatively regulate the function of these organs which were especially important for mammal reproduction. Further, it was reported that the hypothalamic-pituitary-gonadal axis (HPG) is the most important system controlling the secretion of the sex hormones gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in mammals [ 43 , 44 ]. GnRH, FSH and LH are the most important reproductive hormones controlling the reproductive activities of mammals.…”