Prolactin receptor antagonism in mouse anterior pituitary : effects on cell turnover and 1 prolactin receptor expression 2

14 Since anterior pituitary expresses prolactin receptors, prolactin secreted by lactotropes could 15 exert autocrine or paracrine actions on anterior pituitary cells. In fact, it has been observed that 16 prolactin inhibits its own expression by lactotropes. Our hypothesis is that prolactin participates 17 in the control of anterior pituitary cell turnover. In the present study we explored the action of 18 prolactin on proliferation and apoptosis of anterior pituitary cells and its effect on the expression 19 of prolactin receptor. 20 In order to determine the activity of endogenous prolactin, we evaluated the effect of the 21 competitive prolactin receptor antagonist ∆1-9-G129R-hPRL in vivo, using transgenic mice that 22 constitutively and systemically express this antagonist. The weight of the pituitary gland and the 23 anterior pituitary proliferation index, determined by BrdU incorporation, were higher in 24 transgenic mice expressing the antagonist than in wild type littermates. In addition, blockade of 25 prolactin receptor in vitro by ∆1-9-G129R-hPRL increased proliferation and inhibited apoptosis 26 of somatolactotrope GH3 cells and of primary cultures of male rat anterior pituitary cells 27 including lactotropes. These results suggest that prolactin acts as an autocrine/paracrine 28 antiproliferative and proapoptotic factor in the anterior pituitary gland. 29 In addition, anterior pituitary expression of long isoform of prolactin receptor, measured by real 30 time PCR, increased about 10-fold in transgenic mice expressing the prolactin receptor 31 antagonist, whereas only modest increase of S3 short isoform expression was observed. These 32 results suggest that endogenous prolactin may regulate its own biological actions in the anterior 33 pituitary by inhibiting the expression of the long isoform of the prolactin receptor. 34 In conclusion, our observations suggest that prolactin is involved in the maintenance of 35 physiological cell renewal in the anterior pituitary. Alterations in this physiological role of 36 prolactin could contribute to pituitary tumor development. 37