title: Prolactin induces apoptosis of lactotropes in female rodents.
abstract: Anterior pituitary cell turnover occurring during female sexual cycle is a poorly understood process that involves complex regulation of cell proliferation and apoptosis by multiple hormones. In rats, the prolactin (PRL) surge that occurs at proestrus coincides with the highest apoptotic rate. Since anterior pituitary cells express the prolactin receptor (PRLR), we aimed to address the actual role of PRL in the regulation of pituitary cell turnover in cycling females. We showed that acute hyperprolactinemia induced in ovariectomized rats using PRL injection or dopamine antagonist treatment rapidly increased apoptosis and decreased proliferation specifically of PRL producing cells (lactotropes), suggesting a direct regulation of these cell responses by PRL. To demonstrate that apoptosis naturally occurring at proestrus was regulated by transient elevation of endogenous PRL levels, we used PRLR-deficient female mice (PRLRKO) in which PRL signaling is totally abolished. According to our hypothesis, no increase in lactotrope apoptotic rate was observed at proestrus, which likely contributes to pituitary tumorigenesis observed in these animals. To decipher the molecular mechanisms underlying PRL effects, we explored the isoform-specific pattern of PRLR expression in cycling wild type females. This analysis revealed dramatic changes of long versus short PRLR ratio during the estrous cycle, which is particularly relevant since these isoforms exhibit distinct signaling properties. This pattern was markedly altered in a model of chronic PRLR signaling blockade involving transgenic mice expressing a pure PRLR antagonist (TGΔ1-9-G129R-hPRL), providing evidence that PRL regulates the expression of its own receptor in an isoform-specific manner. Taken together, these results demonstrate that i) the PRL surge occurring during proestrus is a major proapoptotic signal for lactotropes, and ii) partial or total deficiencies in PRLR signaling in the anterior pituitary may result in pituitary hyperplasia and eventual prolactinoma development, as observed in TGΔ1-9-G129R-hPRL and PRLRKO mice, respectively.
authors.affiliation: Instituto de Investigaciones Biomédicas, UBA-CONICET, Paraguay, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Jimena
authors.initials: J
authors.lastname: Ferraris
authors.affiliation: Instituto de Investigaciones Biomédicas, UBA-CONICET, Paraguay, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Sandra
authors.initials: S
authors.lastname: Zárate
authors.affiliation: Instituto de Investigaciones Biomédicas, UBA-CONICET, Paraguay, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Jaita
authors.affiliation: INSERM, Unit 1151, Institut Necker Enfants Malades (INEM), Team "PRL/GH Pathophysiology", University Paris Descartes, Sorbonne Paris Cité, Faculty of Medicine, Bâtiment LERICHE, 14 Rue Maria Helena Vieira Da Silva, CS61431, 75993 Paris Cedex 14, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Boutillon
authors.affiliation: INSERM, Unit 1151, Institut Necker Enfants Malades (INEM), Team "PRL/GH Pathophysiology", University Paris Descartes, Sorbonne Paris Cité, Faculty of Medicine, Bâtiment LERICHE, 14 Rue Maria Helena Vieira Da Silva, CS61431, 75993 Paris Cedex 14, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Bernadet
authors.affiliation: INSERM U693 and Université Paris-Sud, Faculté de Médecine Paris-Sud, UMR-S693, Le Kremlin-Bicêtre, F-94276 France.
authors.forename: Julien
authors.initials: J
authors.lastname: Auffret
authors.affiliation: Instituto de Investigaciones Biomédicas, UBA-CONICET, Paraguay, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Adriana
authors.initials: A
authors.lastname: Seilicovich
authors.affiliation: INSERM U693 and Université Paris-Sud, Faculté de Médecine Paris-Sud, UMR-S693, Le Kremlin-Bicêtre, F-94276 France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Binart
authors.affiliation: INSERM, Unit 1151, Institut Necker Enfants Malades (INEM), Team "PRL/GH Pathophysiology", University Paris Descartes, Sorbonne Paris Cité, Faculty of Medicine, Bâtiment LERICHE, 14 Rue Maria Helena Vieira Da Silva, CS61431, 75993 Paris Cedex 14, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Goffin
authors.affiliation: Instituto de Investigaciones Biomédicas, UBA-CONICET, Paraguay, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pisera
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D055786:Gene Knockout Techniques; D052682:Lactotrophs / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D011388:Prolactin / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011981:Receptors, Prolactin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D011981:Receptors, Prolactin; D011388:Prolactin