Prolactin receptor antagonism in mouse anterior pituitary: effects on cell turnover and prolactin receptor expression

Abstract

Since anterior pituitary expresses prolactin receptors, prolactin secreted by lactotropes could exert autocrine or paracrine actions on anterior pituitary cells. In fact, it has been observed that prolactin inhibits its own expression by lactotropes. Our hypothesis is that prolactin participates in the control of anterior pituitary cell turnover. In the present study, we explored the action of prolactin on proliferation and apoptosis of anterior pituitary cells and its effect on the expression of the prolactin receptor. To determine the activity of endogenous prolactin, we evaluated the effect of the competitive prolactin receptor antagonist Δ1-9-G129R-hPRL in vivo, using transgenic mice that constitutively and systemically express this antagonist. The weight of the pituitary gland and the anterior pituitary proliferation index, determined by BrdU incorporation, were higher in transgenic mice expressing the antagonist than in wild-type littermates. In addition, blockade of prolactin receptor in vitro by Δ1-9-G129R-hPRL increased proliferation and inhibited apoptosis of somatolactotrope GH3 cells and of primary cultures of male rat anterior pituitary cells, including lactotropes. These results suggest that prolactin acts as an autocrine/paracrine antiproliferative and proapoptotic factor in the anterior pituitary gland. In addition, anterior pituitary expression of the long isoform of the prolactin receptor, measured by real-time PCR, increased about 10-fold in transgenic mice expressing the prolactin receptor antagonist, whereas only a modest increase in the S3 short-isoform expression was observed. These results suggest that endogenous prolactin may regulate its own biological actions in the anterior pituitary by inhibiting the expression of the long isoform of the prolactin receptor. In conclusion, our observations suggest that prolactin is involved in the maintenance of physiological cell renewal in the anterior pituitary. Alterations in this physiological role of prolactin could contribute to pituitary tumor development.

Use of Prolactin Receptor Antagonist to Better Understand Prolactin Regulation of Pituitary Homeostasis

“…1b). Thanks to this unique molecular tool, we were able to show that PRL acts as a paracrine/autocrine antiproliferative and proapoptotic factor on primary cultures of male rat anterior pituitary cells, specifically but not exclusively on lactotropes [71]. These findings definitely confirmed that the pituitary hyperplasia observed in D2R KO mice is not generated by a PRL proliferative action as had been initially proposed [79].…”

“…Prolactin receptors are expressed by anterior pituitary cells [68,69,70,71]; therefore, one of the primary target cells PRL meets once it is secreted are lactotropes [72]. Prolactin receptor signaling inhibits PRL synthesis at the transcriptional level in lactotrope cells, which involves specific pituitary transcription factors [73].…”

“…Prolactin regulates expression of its own receptor in several tissues, such as hypothalamus [35,36,37,88], ovary [89], brain [70], fallopian tubes [90] and pancreas [91]. Anterior pituitary cells from both mice [71,90] and rats [68,69] express both PRLR isoforms. In male mouse pituitary, the long PRLR is the main isoform expressed, representing about 90% of total pituitary PRLR [71].…”

“…Anterior pituitary cells from both mice [71,90] and rats [68,69] express both PRLR isoforms. In male mouse pituitary, the long PRLR is the main isoform expressed, representing about 90% of total pituitary PRLR [71]. Interestingly enough, chronic expression of Del1-9-G129R-hPRL in transgenic mice leads to a 10-fold increase in long PRLR versus only a 2-fold increase of short PRLRmRNA expression, indicating that PRL regulates the expression of its receptor in an isoform-specific manner [71].…”

Prolactin prevents hepatocellular carcinoma by restricting innate immune activation of c-Myc in mice

“…Based on the above observations, we chose the murine liver cell lines Hepa 1-6 and AML12, except where noted for the functional PRL studies below. There are at least three known splice variants of PRLR-S in mice and two in humans (15,16). In mice, we found that variant S3 comprised…”