title: Constitutive activation of transforming growth factor Beta receptor 1 in the mouse uterus impairs uterine morphology and function.
abstract: Despite increasing evidence pointing to the essential involvement of the transforming growth factor beta (TGFB) superfamily in reproduction, a definitive role of TGFB signaling in the uterus remains to be unveiled. In this study, we generated a gain-of-function mouse model harboring a constitutively active (CA) TGFB receptor 1 (TGFBR1), the expression of which was conditionally induced by the progesterone receptor (Pgr)-Cre recombinase. Overactivation of TGFB signaling was verified by enhanced phosphorylation of SMAD2 and increased expression of TGFB target genes in the uterus. TGFBR1 Pgr-Cre CA mice were sterile. Histological, cellular, and molecular analyses demonstrated that constitutive activation of TGFBR1 in the mouse uterus promoted formation of hypermuscled uteri. Accompanying this phenotype was the upregulation of a battery of smooth muscle genes in the uterus. Furthermore, TGFB ligands activated SMAD2/3 and stimulated the expression of a smooth muscle maker gene, alpha smooth muscle actin (ACTA2), in human uterine smooth muscle cells. Immunofluorescence microscopy identified a marked reduction of uterine glands in TGFBR1 Pgr-Cre CA mice within the endometrial compartment that contained myofibroblast-like cells. Thus, constitutive activation of TGFBR1 in the mouse uterus caused defects in uterine morphology and function, as evidenced by abnormal myometrial structure, dramatically reduced uterine glands, and impaired uterine decidualization. These results underscore the importance of a precisely controlled TGFB signaling system in establishing a uterine microenvironment conducive to normal development and function.
authors.affiliation: Department of Veterinary Integrative Biosciences, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas.
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Veterinary Integrative Biosciences, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas.
authors.forename: Samantha
authors.initials: S
authors.lastname: Duran
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: John P
authors.initials: JP
authors.lastname: Lydon
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
authors.affiliation: Department of Veterinary Integrative Biosciences, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Burghardt
authors.affiliation: Department of Molecular & Cellular Medicine, Texas A&M Health Science Center, Texas A&M University, College Station, Texas.
authors.forename: Kayla J
authors.initials: KJ
authors.lastname: Bayless
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre Léon Bérard, Lyon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Bartholin
authors.affiliation: Department of Veterinary Integrative Biosciences, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas qli@cvm.tamu.edu.
authors.forename: Qinglei
authors.initials: Q
authors.lastname: Li
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D014599:Uterus / Q000033:anatomy & histology* / Q000378:metabolism / Q000502:physiology*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse
keywords: development; endometrium; female reproductive tract; growth factors; infertility; myometrium; transforming growth factor beta; uterine gland; uterus