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Hippo Signaling Disruption and Akt Stimulation of Ovarian Follicles for Infertility Treatment

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Hippo Signaling Disruption and Akt Stimulation of Ovarian Follicles for Infertility Treatment Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment Kazuhiro Kawamuraa,b,1,2, Yuan Chengc,1, Nao Suzukia, Masashi Deguchic, Yorino Satoa,c, Seido Takaea,c, Chi-hong Hoc, Nanami Kawamurab,d, Midori Tamuraa, Shu Hashimotoe, Yodo Sugishitaa, Yoshiharu Morimotoe, Yoshihiko Hosoif, Nobuhito Yoshiokaa, Bunpei Ishizukad,2, and Aaron J. Hsuehc,2 aDepartment of Obstetrics and Gynecology and dDepartment of Advanced Reproductive Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216-8511, Japan; bDepartment of Obstetrics and Gynecology, Akita University Graduate School of Medicine, Akita 010-8543, Japan; cProgram of Reproductive and Stem Cell Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305-5317; eIVF Namba Clinic, Osaka, Osaka 550-0015, Japan; and fGraduate School of Biology-Oriented Science and Technology, Kinki University, Wakayama, Wakayama 649-6493, Japan Edited by John J. Eppig, The Jackson Laboratory, Bar Harbor, ME, and approved August 21, 2013 (received for review July 8, 2013) Primary ovarian insufficiency (POI) and polycystic ovarian syn- (BIRC) apoptosis inhibitors (7). CCN proteins, in turn, stimulate drome are ovarian diseases causing infertility. Although there is cell growth, survival, and proliferation (10). no effective treatment for POI, therapies for polycystic ovarian Using a murine model, we now demonstrated the promo- syndrome include ovarian wedge resection or laser drilling to tion of follicle growth following ovarian fragmentation and induce follicle growth. Underlying mechanisms for these disrup- allo-transplantation. Ovarian fragmentation increased actin poly- tive procedures are unclear. Here, we explored the role of the merization, decreased phospho-YAP (pYAP) levels, increased conserved Hippo signaling pathway that serves to maintain nuclear localization of YAP, as well as enhanced expression of optimal size across organs and species. We found that fragmen- CCN growth factors and BIRC apoptosis inhibitors. Frag- tation of murine ovaries promoted actin polymerization and mentation-induced follicle growth was partially blocked by CCN2 disrupted ovarian Hippo signaling, leading to increased expression antibodies and verteporfin, a small molecule that inhibits inter- of downstream growth factors, promotion of follicle growth, and actions of YAP with TEAD transcriptional factors (11). the generation of mature oocytes. In addition to elucidating Studies using phosphatase and tensin homolog deleted from mechanisms underlying follicle growth elicited by ovarian dam- chromosome 10 (PTEN) deletion mice indicated the stimulatory age, we further demonstrated additive follicle growth when roles of Akt signaling in the development of primordial (12) and ovarian fragmentation was combined with Akt stimulator treat- secondary follicles (13). Our earlier report demonstrated the ments. We then extended results to treatment of infertility in POI ability of Akt stimulators to activate dormant primordial follicles patients via disruption of Hippo signaling by fragmenting ovaries (14). We now demonstrated additive increases in follicle growth followed by Akt stimulator treatment and autografting. We when ovarian fragments containing secondary and smaller fol- successfully promoted follicle growth, retrieved mature oocytes, licles were treated with Akt stimulators. Using this in vitro ac- and performed in vitro fertilization. Following embryo transfer, tivation (IVA) method for infertility treatment of POI patients, a healthy baby was delivered. The ovarian fragmentation–in vitro we successfully promoted the growth of residual follicles in activation approach is not only valuable for treating infertility of autografts and report a viable birth following oocyte retrieval POI patients but could also be useful for middle-aged infertile and in vitro fertilization (IVF)–embryo transfer. women, cancer patients undergoing sterilizing treatments, and other conditions of diminished ovarian reserve. Significance ovary | aging | YAP | CCN2 | PTEN Human ovaries hold follicles containing oocytes. When follicles etween 5% and 10% of reproductive-age women are infertile mature, they release eggs for fertilization. Patients with pri- fi Bdue to polycystic ovarian syndrome (PCOS) (1), whereas 1% mary ovarian insuf ciency develop menopausal symptoms at of them suffer from infertility due to primary ovarian insuffi- less than 40 y of age. They have few remaining follicles and their only chance for bearing a baby is through egg donation. ciency (POI) (2, 3). They are infertile due to aberrant follicle Kawamura et al. demonstrated that Hippo and Akt signaling growth. As early as the 1930s, ovarian wedge resection (4) was pathways regulate follicle growth. Using an in vitro activation used for PCOS treatment to induce follicle growth, followed by approach, they first removed ovaries from infertile patients, “ ” recent success based on ovarian drilling by diathermy or laser followed by fragmentation to disrupt Hippo signaling and drug (5). In addition, ovarian cortices are routinely fragmented to allow treatment to stimulate Akt signaling. After grafting ovarian better freezing and grafting for fertility preservation in cancer pa- tissues back to patients, they found rapid follicle growth in tients who underwent sterilizing treatment (6). Subsequent auto- some patients and successfully retrieved mature eggs. After in transplantation of ovarian fragments is associated with spontaneous vitro fertilization and embryo transfer, a live birth is now follicle growth. Underlying mechanisms for these disruptive pro- reported. cedures to promote follicle growth are, however, unclear. The Hippo signaling pathway is essential to maintain optimal Author contributions: K.K., Y.C., and A.J.H. designed research; K.K., Y.C., N.S., M.D., – Y. Sato, S.T., C.-h.H., N.K., M.T., S.H., Y. Sugishita, Y.M., Y.H., N.Y., and B.I. performed organ size and is conserved in all metazoan animals (7 9). Hippo research; K.K., Y.C., M.D., Y. Sato, and A.J.H. analyzed data; and K.K., Y.C., and A.J.H. signaling consists of several negative growth regulators acting in wrote the paper. a kinase cascade that ultimately phosphorylates and inactivates The authors declare no conflict of interest. key Hippo signaling effectors, Yes-associated protein(YAP)/ This article is a PNAS Direct Submission. transcriptional coactivator with PDZ-binding motif(TAZ). When 1K.K. and Y.C. contributed equally to this work. Hippo signaling is disrupted, decreases in YAP phosphorylation 2To whom correspondence may be addressed. E-mail: [email protected], increase nuclear levels of YAP. YAP acts in concert with TEAD [email protected], or [email protected]. transcriptional factors to increase downstream CCN growth This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. factors and baculoviral inhibitors of apoptosis repeat containing 1073/pnas.1312830110/-/DCSupplemental. 17474–17479 | PNAS | October 22, 2013 | vol. 110 | no. 43 www.pnas.org/cgi/doi/10.1073/pnas.1312830110 Downloaded by guest on September 27, 2021 Results that induction of extra F-actin formation disrupted Hippo sig- Drosophila Ovarian Fragmentation Promoted Follicle Growth. We fragmented naling and induced overgrowth in imaginal discs and A ovaries from juvenile (day 10) mice containing secondary and human HeLa cells (15, 16). As shown in Fig. 2 , a transient smaller follicles, followed by allo-transplantation under kidney increase in ratios of F-actin to G-actin was detected at 1 h after capsules of adult hosts. As shown in Fig. 1A, major increases in ovarian fragmentation. The Hippo signaling kinase cascade graft sizes were evident after cutting ovaries into three pieces and phosphorylates YAP to promote its cytoplasmic localization and grafting for 5 d compared with paired intact ovaries. Graft degradation, thus decreasing its transcriptional actions. When weights increased after cutting ovaries into 2–4 pieces or in- Hippo signaling is disrupted, decreases in pYAP increase nuclear cubating fragments for up to 24 h before grafting (Fig. 1B). YAP levels (17). After ovarian fragmentation and incubation for A 1 h, decreases in pYAP levels and pYAP to total YAP ratios Histological analyses (Fig. S1 ) and follicle counting of grafts B (Fig. 1C and Fig. S1B) indicated a loss of total follicles following were evident (Fig. 2 ), suggesting Hippo signaling disruption. In fragmentation/grafting. However, major increases in the per- intact ovaries from day 10 mice, immunohistochemical staining indicated that YAP was localized in the cytoplasm of granulosa centage of late secondary and antral/preovulatory follicles were cells in most follicles at primary and secondary stages (Fig. S2D). evident, accompanied by decreases in primordial follicles (Fig. C At 4 h after fragmentation, nuclear staining of YAP was found in 1 ). Compared with day 10 ovaries, the grafting procedure led to granulosa cells of primary and secondary follicles. decreases in absolute number of primordial, primary, and early B Disruption of Hippo signaling leads to increased expression of secondary follicles (Fig. S1 ). Furthermore, cutting/grafting of downstream CCN growth factors and BIRC apoptosis inhibitors ovaries from older mice, including those containing early antral C D (7, 8). As shown in Fig. 2 , ovarian fragmentation and sub- follicles from day 23 animals, also increased graft weights (Fig. 1 ). sequent
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