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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.
AuthorsYuan Cheng, Yi Feng, Lina Jansson, Yorino Sato, Masashi Deguchi, Kazuhiro Kawamura, Aaron J Hsueh
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 29 Issue 6 Pg. 2423-30 (Jun 2015) ISSN: 1530-6860 [Electronic] United States
PMID25690654 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright© FASEB.
Chemical References
  • Actins
  • Adaptor Proteins, Signal Transducing
  • Depsipeptides
  • Lysophospholipids
  • Phosphoproteins
  • Yap protein, mouse
  • jasplakinolide
  • Connective Tissue Growth Factor
  • sphingosine 1-phosphate
  • Hippo protein, mouse
  • Protein-Serine-Threonine Kinases
  • Sphingosine
Topics
  • Actins (metabolism)
  • Active Transport, Cell Nucleus (drug effects)
  • Adaptor Proteins, Signal Transducing (genetics, metabolism)
  • Animals
  • Connective Tissue Growth Factor (genetics, metabolism)
  • Depsipeptides (pharmacology)
  • Female
  • Gene Expression (drug effects)
  • Humans
  • Immunohistochemistry
  • Lysophospholipids (pharmacology)
  • Mice, SCID
  • Mice, Transgenic
  • Mutation
  • Organ Culture Techniques
  • Ovarian Follicle (drug effects, growth & development, metabolism)
  • Ovary (growth & development, metabolism, transplantation)
  • Phosphoproteins (genetics, metabolism)
  • Polymerization (drug effects)
  • Protein-Serine-Threonine Kinases (metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction (drug effects)
  • Sphingosine (analogs & derivatives, pharmacology)

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