title: Prolactin signaling through the short form of its receptor represses forkhead transcription factor FOXO3 and its target gene galt causing a severe ovarian defect.
abstract: Prolactin (PRL) is a hormone with over 300 biological activities. Although the signaling pathway downstream of the long form of its receptor (RL) has been well characterized, little is known about PRL actions upon activation of the short form (RS). Here, we show that mice expressing only RS exhibit an ovarian phenotype of accelerated follicular recruitment followed by massive follicular death leading to premature ovarian failure. Consequently, RS-expressing ovaries of young adults are depleted of functional follicles and formed mostly by interstitium. We also show that activation of RS represses the expression of the transcription factor Forkhead box O3 (FOXO3) and that of the enzyme galactose-1-phosphate uridyltransferase (Galt), two proteins known to be essential for normal follicular development. Our finding that FOXO3 regulates the expression of Galt and enhances its transcriptional activity indicates that it is the repression of FOXO3 by PRL acting through RS that prevents Galt expression in the ovary and causes follicular death. Coexpression of RL with RS prevents PRL inhibition of Galt, and the ovarian defect is no longer seen in RS transgenic mice that coexpress RL, suggesting that RL prevents RS-induced ovarian impairment. In summary, we show that PRL signals through RS and causes, in the absence of RL, a severe ovarian pathology by repressing the expression of FOXO3 and that of its target gene Galt. We also provide evidence of a link between the premature ovarian failure seen in mice expressing RS and in mice with FOXO3 gene deletion as well as in human with Galt mutation.
authors.affiliation: Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, 835 South Wolcott, M/C 901, Chicago, IL 60612, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Halperin
authors.forename: Y Sangeeta
authors.initials: YS
authors.lastname: Devi
authors.forename: Sangeeta Y
authors.initials: SY
authors.lastname: Devi
authors.forename: Shai
authors.initials: S
authors.lastname: Elizur
authors.forename: Carlos
authors.initials: C
authors.lastname: Stocco
authors.forename: Aurora
authors.initials: A
authors.lastname: Shehu
authors.forename: Diane
authors.initials: D
authors.lastname: Rebourcet
authors.forename: Terry G
authors.initials: TG
authors.lastname: Unterman
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Leslie
authors.forename: Jamie
authors.initials: J
authors.lastname: Le
authors.forename: Nadine
authors.initials: N
authors.lastname: Binart
authors.forename: Geula
authors.initials: G
authors.lastname: Gibori
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D006080:Ovarian Follicle / Q000254:growth & development / Q000378:metabolism; D010053:Ovary / Q000378:metabolism* / Q000473:pathology; D011388:Prolactin / Q000097:blood / Q000502:physiology*; D011981:Receptors, Prolactin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic; D005694:UTP-Hexose-1-Phosphate Uridylyltransferase / Q000235:genetics / Q000378:metabolism
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D011981:Receptors, Prolactin; D011388:Prolactin; D005694:UTP-Hexose-1-Phosphate Uridylyltransferase