title: Conditional deletion of Tsc1 in the female reproductive tract impedes normal oviductal and uterine function by enhancing mTORC1 signaling in mice.
abstract: Heightened mammalian target of rapamycin complex 1 (mTORC1) activity by genetic deletion of its direct inhibitor, Tsc1, is associated with aberrant development and dysfunction of the female reproductive tract in mice. Here, we compared the phenotypes of mice with conditional deletion of Tsc1 in the female reproductive tract by either progesterone receptor (PR)-Cre (Tsc1(PR(d/d))), which inactivates Tsc1 in all major cell types in the uterus (epithelium, stroma and myometrium), or anti-Mullerian hormone type 2 receptor (Amhr2)-Cre (Tsc1(Amhr2(d/d))), which inactivates stromal and myometrial Tsc1. Tsc1(PR(d/d)) and Tsc1(Amhr2(d/d)) females are infertile resulting from oviductal hyperplasia, retention of embryos in the oviduct and implantation failure. In contrast to the appropriate embryonic development after fertilization seen in Tsc1(Amhr2(d/d)) females, embryo development was disrupted in Tsc1(PR(d/d)) females. In addition, uteri in Tsc1(PR(d/d)) and Tsc1(Amhr2(d/d)) females showed epithelial hyperplasia but not endometrial cancer. In conclusion, Tsc1(PR(d/d)) and Tsc1(Amhr2(d/d)) have overlapping yet distinct phenotypes in the context of compartment-specific deletion of Tsc1.
authors.affiliation: Division of Reproductive Sciences, The Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, MLC 7045, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. takiko.daikoku@cchmc.org
authors.forename: Takiko
authors.initials: T
authors.lastname: Daikoku
authors.forename: Mikihiro
authors.initials: M
authors.lastname: Yoshie
authors.forename: Huirong
authors.initials: H
authors.lastname: Xie
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Sun
authors.forename: Jeeyeon
authors.initials: J
authors.lastname: Cha
authors.forename: Lora Hedrick
authors.initials: LH
authors.lastname: Ellenson
authors.forename: Sudhansu K
authors.initials: SK
authors.lastname: Dey
mesh_terms: D000818:Animals; D004958:Estradiol / Q000097:blood; D005260:Female; D005307:Fertilization in Vitro; D007150:Immunohistochemistry; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008817:Mice, Mutant Strains; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D010053:Ovary / Q000378:metabolism; D010057:Oviducts / Q000378:metabolism*; D011374:Progesterone / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014599:Uterus / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D011374:Progesterone; D004958:Estradiol; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: Tsc1; mouse; ovary; oviduct; uterus