title: Actin polymerization-enhancing drugs promote ovarian follicle growth mediated by the Hippo signaling effector YAP.
abstract: Hippo signaling pathway consists of conserved serine/threonine kinases to maintain optimal organ sizes. Studies have demonstrated that fragmentation of murine ovaries increases actin polymerization and disrupts Hippo signaling, leading to nuclear translocation of Hippo signaling effector Yes-associated protein (YAP) in ovarian follicles and follicle growth. For patients with polycystic ovarian syndrome showing follicle arrest, ovarian wedge resection and laser drilling promote follicle growth. Because these damaging procedures likely involve actin polymerization, we tested whether actin polymerization-promoting drugs could promote YAP translocation and stimulate follicle growth. Treatment of murine ovaries with μM Jasplakinolide (JASP), an actin polymerization-promoting cyclic peptide, or sphingosine-1-phosphate (S1P), a follicular fluid constituent known to promote actin polymerization, increased the conversion of globular actin to the filamentous form, followed by increased nuclear YAP and expression of downstream connective tissue growth factor (CCN2). After short-term treatments with JASP or S1P, in vitro cultured and in vivo grafted ovaries showed follicle growth. Furthermore, induction of constitutively active YAP in ovarian grafts of transgenic mice enhanced follicle development, whereas treatment of human ovarian cortices with JASP or S1P increased CCN2 expression. Thus, JASP and S1P stimulate follicle growth and are potential therapeutic agents for treating polycystic ovarian syndrome and other ovarian disorders.
authors.affiliation: *Department of Obstetrics and Gynecology and Department of Otolaryngology, Stanford University School of Medicine, Stanford, California, USA; Department of Obstetrics and Gynecology, St. Mariana University, Kawasaki, Japan; and Department of Obstetrics and Gynecology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: *Department of Obstetrics and Gynecology and Department of Otolaryngology, Stanford University School of Medicine, Stanford, California, USA; Department of Obstetrics and Gynecology, St. Mariana University, Kawasaki, Japan; and Department of Obstetrics and Gynecology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Yi
authors.initials: Y
authors.lastname: Feng
authors.affiliation: *Department of Obstetrics and Gynecology and Department of Otolaryngology, Stanford University School of Medicine, Stanford, California, USA; Department of Obstetrics and Gynecology, St. Mariana University, Kawasaki, Japan; and Department of Obstetrics and Gynecology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Lina
authors.initials: L
authors.lastname: Jansson
authors.affiliation: *Department of Obstetrics and Gynecology and Department of Otolaryngology, Stanford University School of Medicine, Stanford, California, USA; Department of Obstetrics and Gynecology, St. Mariana University, Kawasaki, Japan; and Department of Obstetrics and Gynecology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Yorino
authors.initials: Y
authors.lastname: Sato
authors.affiliation: *Department of Obstetrics and Gynecology and Department of Otolaryngology, Stanford University School of Medicine, Stanford, California, USA; Department of Obstetrics and Gynecology, St. Mariana University, Kawasaki, Japan; and Department of Obstetrics and Gynecology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Deguchi
authors.affiliation: *Department of Obstetrics and Gynecology and Department of Otolaryngology, Stanford University School of Medicine, Stanford, California, USA; Department of Obstetrics and Gynecology, St. Mariana University, Kawasaki, Japan; and Department of Obstetrics and Gynecology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kawamura
authors.affiliation: *Department of Obstetrics and Gynecology and Department of Otolaryngology, Stanford University School of Medicine, Stanford, California, USA; Department of Obstetrics and Gynecology, St. Mariana University, Kawasaki, Japan; and Department of Obstetrics and Gynecology, Akita University Graduate School of Medicine, Akita, Japan aaron.hsueh@stanford.edu.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Hsueh
mesh_terms: D000199:Actins / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D000090683:Hippo Signaling Pathway; D006801:Humans; D007150:Immunohistochemistry; D008246:Lysophospholipids / Q000494:pharmacology; D016513:Mice, SCID; D008822:Mice, Transgenic; D009154:Mutation; D009924:Organ Culture Techniques; D006080:Ovarian Follicle / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D010053:Ovary / Q000254:growth & development / Q000378:metabolism / Q000637:transplantation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D058105:Polymerization / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000091102:YAP-Signaling Proteins
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D047630:Depsipeptides; D008246:Lysophospholipids; D010750:Phosphoproteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; C057531:jasplakinolide; D055513:Connective Tissue Growth Factor; C060506:sphingosine 1-phosphate; D017346:Protein Serine-Threonine Kinases; D013110:Sphingosine
keywords: Jasplakinolide; connective tissue growth factor; sphingosine-1-phosphate