title: Selective deletion of Pten in theca-interstitial cells leads to androgen excess and ovarian dysfunction in mice.
abstract: Theca cell-selective Pten mutation (tPtenMT) in mice resulted in increases in PDK1 and Akt phosphorylation, indicating an over-activation of PI3K signaling in the ovaries. These mice displayed elevated androgen levels, ovary enlargement, antral follicle accumulation, early fertility loss and increased expression of Lhcgr and genes that are crucial to androgenesis. These abnormalities were partially reversed by treatments of PI3K or Akt inhibitor. LH actions in Pten deficient theca cells were potentiated. The phosphorylation of Foxo1 was increased, while the binding of Foxo1 to forkhead response elements in the Lhcgr promoter was reduced in tPtenMT theca cells, implying a mechanism by which PI3K/Akt-induced upregulation of Lhcgr in theca cells might be mediated by reducing the inhibitory effect of Foxo1 on the Lhcgr promoter. The phenotype of tPtenMT females is reminiscent of human PCOS and suggests that dysregulated PI3K cascade in theca cells may be involved in certain types of PCOS pathogenesis.
authors.affiliation: Division of Life Sciences and Center for Animal Nutrigenomics & Applied Animal Nutrition, Alltech Inc., Nicholasville, KY 40356, USA.
authors.forename: Zi-Jian
authors.initials: ZJ
authors.lastname: Lan
authors.affiliation: Department of OB/GYN & Women's Health, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Krause
authors.affiliation: Department of OB/GYN & Women's Health, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Redding
authors.affiliation: Department of OB/GYN & Women's Health, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of OB/GYN & Women's Health, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: G Z
authors.initials: GZ
authors.lastname: Wu
authors.affiliation: Birth Defects Center, Department of Molecular, Cellular and Craniofacial Biology, University of Louisville School of Dentistry, Louisville, KY 40202, USA.
authors.forename: H X
authors.initials: HX
authors.lastname: Zhou
authors.affiliation: Department of OB/GYN & Women's Health, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: H C
authors.initials: HC
authors.lastname: Bohler
authors.affiliation: Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: C
authors.initials: C
authors.lastname: Ko
authors.affiliation: Department of Pediatrics, The University of Texas at Austin Dell Medical School, Austin, TX 78712, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Cooney
authors.affiliation: Central Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200000, China.
authors.forename: Junmei
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of OB/GYN & Women's Health, University of Louisville School of Medicine, Louisville, KY 40202, USA. Electronic address: zhenmin.lei@louisville.edu.
authors.forename: Z M
authors.initials: ZM
authors.lastname: Lei
mesh_terms: D000375:Aging / Q000378:metabolism; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D002747:Chlorpropamide / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D005298:Fertility; D000071161:Forkhead Box Protein O1 / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D007986:Luteinizing Hormone / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008954:Models, Biological; D010053:Ovary / Q000187:drug effects / Q000503:physiopathology*; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011974:Receptors, LH / Q000235:genetics / Q000378:metabolism; D013256:Steroids / Q000096:biosynthesis; D013739:Testosterone / Q000097:blood; D013799:Theca Cells / Q000187:drug effects / Q000378:metabolism*; D000096926:Benzenesulfonamides
chemical_list: D000728:Androgens; D002747:Chlorpropamide; D000071161:Forkhead Box Protein O1; D007986:Luteinizing Hormone; D051059:PTEN Phosphohydrolase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011974:Receptors, LH; D013256:Steroids; D013739:Testosterone; C111224:API 2; D000096926:Benzenesulfonamides; C467200:Foxo1 protein, mouse; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse
keywords: Conditional knockout; LHCGR; Ovary theca cells; PCOS; PI3K; Pten