Uncovering the missing link in molecular mechanisms regulating female reproductive function

• Project/Area Number: 16K08603
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: National Center for Child Health and Development
• Principal Investigator: Miyado Mami 国立研究開発法人国立成育医療研究センター, 分子内分泌研究部, 上級研究員 (00386252)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 生殖機能 / 卵巣ステロイド / MAMLD1 / NR5A1 / 非古典的男性ホルモン / CD9 / 生殖

Outline of Final Research Achievements

In order to identify missing pieces hidden in already known mechanisms of female reproductive function, we performed this study using a set of disease model animals and samples obtained from patients. Subsequently, we obtained remarkable results as followings: (1) Pituitary hormone regulates the Mamld1 expression in the mouse ovary; (2) The p.R92W variant of NR5A1/Nr5a1 induces testis formation specifically in women; (3) 11-oxygenated C19 steroids are clinically important as circulating androgens in patients with polycystic ovarian syndrome; (4) Autophagy-disrupted LC3 abundance worsens the oocyte quality with age; and (5) CD9 functions in regenerating the uterine epithelium.

Academic Significance and Societal Importance of the Research Achievements

本研究では、遺伝子機能の変化やホルモンバランスの変化が雌性生殖機能に与える影響を明らかにした。さらに、モデル動物と疾患患者の解析を行うことで、生物種間における雌性生殖機能に与える影響の共通性と多様性を見出した。本研究の意義として、単一遺伝子の機能低下により引き起こされる疾患発症機序の解明が挙げられる。本研究の成果は、性分化疾患や不妊症などの内分泌関連疾患の発症機序の解明に結び付くことが期待される。

Research Products

• [Journal Article] Losing maleness: Somatic Y chromosome loss at every stage of a man’s life. (2019)
  • Author(s): Miyado M and Fukami M.
  • Journal Title: FASEB BioAdv. (in press) Volume: 印刷中 Pages: 350-352
  • DOI: 10.1096/fba.2019-00006
  • Peer Reviewed / Open Access
• [Journal Article] DNA methylation status of SHOX-flanking CpG islands in healthy individuals and short stature patients with pseudoautosomal copy-number variations. (2019)
  • Author(s): Ogushi K, Hattori A, Suzuki E, Shima H, Izawa M, Yagasaki H, Horikawa R, Uetake K, Umezawa A, Ishii T, Muroya K, Namba N, Tanaka T, Hirano Y, Yamamoto H, Soneda S, Matsubara K, Kagami M, Miyado M and Fukami M.
  • Journal Title: Cytogenet Genome Res. (in press) Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Germline-Derived Gain-of-Function Variants of Gsα-Coding GNAS Gene Identified in Nephrogenic Syndrome of Inappropriate Antidiuresis (2019)
  • Author(s): Miyado Mami、Fukami Maki、Takada Shuji、Terao Miho、Nakabayashi Kazuhiko、Hata Kenichiro、Matsubara Yoichi、Tanaka Yoko、Sasaki Goro、Nagasaki Keisuke、Shiina Masaaki、Ogata Kazuhiro、Masunaga Youhei、Saitsu Hirotomo、Ogata Tsutomu
  • Journal Title: Journal of the American Society of Nephrology Volume: 30 Issue: 5 Pages: 877-889
  • DOI: 10.1681/asn.2018121268
  • Peer Reviewed / Open Access
• [Journal Article] Dihydrotestosterone induces minor transcriptional alterations in genital skin fibroblasts of children with and without androgen insensitivity (2019)
  • Author(s): Tanase-Nakao Kanako、Mizuno Kentaro、Hayashi Yutaro、Kojima Yoshiyuki、Hara Mariko、Matsumoto Kenji、Matsubara Yoichi、Igarashi Maki、Miyado Mami、Fukami Maki
  • Journal Title: Endocrine Journal Volume: 66 Issue: 4 Pages: 387-393
  • DOI: 10.1507/endocrj.EJ18-0494
  • NAID: 130007636463
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] Membrane protein CD9 is repositioned and released to enhance uterine function. (2019)
  • Author(s): Iwai M, Hamatani T, Nakamura A, Kawano N, Kanai S, Kang W, Yoshii N, Odawara Y, Yamada M, Miyamoto Y, Saito T, Saito H, Miyado M, Umezawa A, Miyado K, Tanaka M.
  • Journal Title: Laboratory Investigation Volume: 99 Issue: 2 Pages: 200-209
  • DOI: 10.1038/s41374-018-0145-1
  • Peer Reviewed / Open Access
• [Journal Article] Chemotactic behavior of egg mitochondria in response to sperm fusion in mice (2018)
  • Author(s): Iwai Maki、Harada Yuichirou、Miyabayashi Rinako、Kang Woojin、Nakamura Akihiro、Kawano Natsuko、Miyamoto Yoshitaka、Yamada Mitsutoshi、Hamatani Toshio、Miyado Mami、Yoshida Keiichi、Saito Hidekazu、Tanaka Mamoru、Umezawa Akihiro、Miyado Kenji
  • Journal Title: Heliyon Volume: 4 Issue: 11 Pages: e00944-e00944
  • DOI: 10.1016/j.heliyon.2018.e00944
  • Peer Reviewed / Open Access
• [Journal Article] Degradation of phosphate polymer polyP enhances lactic fermentation in mice. (2018)
  • Author(s): Nakamura A, Kawano N, Motomura K, Kuroda A, Sekiguchi K, Miyado M, Woojin K, Miyamoto Y, Hanai M, Iwai M, Yamada M, Hamatani T, Saito T, Saito H, Tanaka M, Umezawa A, Miyado K.
  • Journal Title: Genes Cells. Volume: 23(10) Issue: 10 Pages: 904-914
  • DOI: 10.1111/gtc.12639
  • Peer Reviewed / Open Access
• [Journal Article] Autophagy-disrupted LC3 abundance leads to death of supporting cells of human oocytes. (2018)
  • Author(s): Kang W, Ishida E, Yamatoya K, Nakamura A, Miyado M, Miyamoto Y, Iwai M, Tatsumi K, Saito T, Saito K, Kawano N, Hamatani T, Umezawa A, Miyado K, Saito H.
  • Journal Title: Biochem Biophys Rep. Volume: 21(15) Pages: 107-114
  • DOI: 10.1016/j.bbrep.2018.08.002
  • Peer Reviewed / Open Access
• [Journal Article] 11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome (2018)
  • Author(s): Yoshida T, Matsuzaki T, Miyado M, Saito K, Iwasa T, Matsubara Y, Ogata T, Irahara M, Fukami M.
  • Journal Title: Endocrine Journal Volume: 65 Issue: 10 Pages: 979-990
  • DOI: 10.1507/endocrj.EJ18-0212
  • NAID: 130007501323
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] 停留精巣の原因遺伝子と環境因子―ゲノム解析の現況と未来． (2018)
  • Author(s): 宮戸真美，深見真紀．
  • Journal Title: 臨床泌尿器科（医学書院） Volume: 72 Pages: 836-839
• [Journal Article] Somatically acquired isodicentric Y and mosaic loss of chromosome Y in a boy with hypospadias. (2018)
  • Author(s): Miyado M, Muroya K, Katsumi M, Saito K, Kon M and Fukami M.
  • Journal Title: Cytogenet Genome Res. (in press) Volume: 印刷中 Issue: 3 Pages: 0-0
  • DOI: 10.1159/000488162
  • Peer Reviewed / Open Access
• [Journal Article] STX2 is a causative gene for nonobstructive azoospermia. (2018)
  • Author(s): Nakamura S, Kobori Y, Ueda Y, Tanaka Y, Ishikawa H, Yoshida A, Katsumi M, Saito K, Nakamura A, Ogata T, Okada H, Nakai H, Miyado M and Fukami M.
  • Journal Title: Hum Mutat. (in press) Volume: 印刷中 Issue: 6 Pages: 0-0
  • DOI: 10.1002/humu.23423
  • Peer Reviewed
• [Journal Article] Ubiquitin-activating enzyme E1 inhibitor PYR-41 retards sperm enlargement after fusion to the egg. (2018)
  • Author(s): Yoshida K, Kang W, Nakamura A, Kawano N, Hanai M, Miyado M, Miyamoto Y, Iwai M, Hamatani T, Saito H, Miyado K and Umezawa A.
  • Journal Title: Reprod Toxicol. Volume: 76 Pages: 71-77
  • DOI: 10.1016/j.reprotox.2018.01.001
  • Peer Reviewed
• [Journal Article] Expression of xenobiotic biomarkers CYP1 family in preputial tissue of patients with hypospadias and phimosis and its association with DNA methylation level of SRD5A2 minimal promoter. (2018)
  • Author(s): Ohsako S, Aiba T, Miyado M, Fukami M, Ogata T, Hayashi Y, Mizuno K and Kojima Y.
  • Journal Title: Arch Environ Contam Toxicol. Volume: 74 Issue: 2 Pages: 240-247
  • DOI: 10.1007/s00244-017-0466-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gain-of-function mutations in G-protein coupled receptor genes associated with human endocrine disorders. (2018)
  • Author(s): Fukami M, Suzuki E, Igarashi M, Miyado M and Ogata T.
  • Journal Title: Clin Endocrinol (Oxf). Volume: 88 Issue: 3 Pages: 351-359
  • DOI: 10.1111/cen.13496
  • Peer Reviewed / Open Access
• [Journal Article] Case of heterotopic cervical pregnancy and total placenta accreta after artificial cycle frozen-thawed embryo transfer. (2018)
  • Author(s): Saito K, Fukami M, Miyado M, Ono I and Sumori K.
  • Journal Title: Reprod Med Biol. Volume: 17 Pages: 89-92
  • Peer Reviewed / Open Access
• [Journal Article] Next-generation sequencing for patients with non-obstructive azoospermia: implications for significant roles of monogenic/oligogenic mutations. (2017)
  • Author(s): Nakamura S, Miyado M, Saito M, Katsumi M, Nakamura A, Kobori Y, Tanaka Y, Ishikawa H, Yoshida A, Okada H, Hata K, Nakabayashi K, Okamura K, Ogata H, Matsubara Y, Ogata T, Nakai H and Fukami M.
  • Journal Title: Andrology. Volume: 5 Issue: 4 Pages: 824-831
  • DOI: 10.1111/andr.12378
  • Peer Reviewed
• [Journal Article] Next generation sequencing and array-based comparative genomic hybridization for molecular diagnosis of pediatric endocrine disorders. (2017)
  • Author(s): Fukami M and Miyado M.
  • Journal Title: Ann Pediatr Endocrinol Metab. Volume: 22 Issue: 2 Pages: 15-19
  • DOI: 10.6065/apem.2017.22.2.90
  • Open Access
• [Journal Article] Knockout of murine Mamld1 impairs testicular growth and daily sperm production but permits normal postnatal androgen production and fertility. (2017)
  • Author(s): Miyado M, Yoshida K, Miyado K, Katsumi M, Saito K, Nakamura S, Ogata T and Fukami M.
  • Journal Title: Int J Mol Sci. Volume: 18 Issue: 6 Pages: 1300-1300
  • DOI: 10.3390/ijms18061300
  • Peer Reviewed / Open Access
• [Journal Article] Paradoxical gain-of-function mutant of the G-protein-coupled receptor PROKR2 promotes early puberty. (2017)
  • Author(s): Fukami M, Suzuki E, Izumi Y, Torii T, Narumi S, Igarashi M, Miyado M, Katsumi M, Fujisawa Y, Nakabayashi K, Hata K, Umezawa A, Matsubara Y, Yamauchi J, Ogata T.
  • Journal Title: Journal of Cellular and Molecular Medicine Volume: - Issue: 10 Pages: 2623-2626
  • DOI: 10.1111/jcmm.13146
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Exosomes versus microexosomes: Shared components but distinct functions (2017)
  • Author(s): Miyado K, Kang W, Yamatoya K, Hanai M, Nakamura A, Mori T, Miyado M, Kawano N
  • Journal Title: J Plant Res Volume: 130 Issue: 3 Pages: 479-483
  • DOI: 10.1007/s10265-017-0907-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Birth weights and Down syndrome in neonates delivered after frozen-thawed embryo transfer: Six-year study (2007-2012) on the national assisted reproduction registry data in Japan (2017)
  • Author(s): Yamatoya K, Saito K, Saito T, Kang W, Nakamura A, Miyado M, Kawano N, Miyamoto Y, Umezawa A, Miyado K, Saito H
  • Journal Title: Reproductive Medicine and Biology Volume: 16 Issue: 2 Pages: 228-234
  • DOI: 10.1002/rmb2.12033
  • Peer Reviewed / Open Access
• [Journal Article] Expression patterns of Fgf8 and Shh in the developing external genitalia of Suncus murinus (2017)
  • Author(s): Miyado M, Miyado K, Nakamura A, Fukami M, Yamada G, Oda SI
  • Journal Title: Reproduction Volume: 153 Issue: 2 Pages: 187-195
  • DOI: 10.1530/rep-16-0231
  • Peer Reviewed / Open Access
• [Journal Article] Identical NR5A1 Missense Mutations in Two Unrelated 46,XX Individuals with Testicular Tissues. (2017)
  • Author(s): Igarashi M, Fukami M et al.
  • Journal Title: Hum Mutat. Volume: 38 Issue: 1 Pages: 39-42
  • DOI: 10.1002/humu.23116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Increased incidence of post-term delivery and Cesarean section after frozen-thawed embryo transfer during a hormone replacement cycle (2016)
  • Author(s): Saito K, Miyado K, Yamatoya K, Kuwahara A, Inoue E, Miyado M, Fukami M, Ishikawa T, Saito T, Kubota T, Saito H
  • Journal Title: J Assist Reprod Genet Volume: 34 Issue: 4 Pages: 465-470
  • DOI: 10.1007/s10815-017-0869-7
  • Peer Reviewed / Open Access
• [Journal Article] The p.R92W variant of NR5A1/Nr5a1 induces testicular development of 46,XX gonads in humans, but not in mice: phenotypic comparison of human patients and mutation-induced mice (2016)
  • Author(s): Miyado M, Inui M, Igarashi M, Katoh-Fukui Y, Takasawa K, Hakoda A, Kanno J, Kashimada K, Miyado K, Tamano M, Ogata T, Takada S, Fukami M
  • Journal Title: Biol Sex Differ Volume: 7 Issue: 1 Pages: 56-56
  • DOI: 10.1186/s13293-016-0114-6
  • Peer Reviewed / Open Access
• [Journal Article] Extra-adrenal induction of <i>Cyp21a1</i> ameliorates systemic steroid metabolism in a mouse model of congenital adrenal hyperplasia (2016)
  • Author(s): Naiki Y, Miyado M, Horikawa R, Katsumata N, Onodera M, Pang S, Ogata T and Fukami M.
  • Journal Title: Endocrine Journal Volume: 63 Issue: 10 Pages: 897-904
  • DOI: 10.1507/endocrj.EJ16-0112
  • NAID: 130005267899
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 多嚢胞性卵巣症候群における非古典的アンドロゲンの意義． (2018)
  • Author(s): 吉田朋子，松崎利也，宮戸真美（代理発表），齊藤和毅，岩佐 武，松原洋一，緒方 勤，苛原 稔，深見真紀．
  • Organizer: 第52回日本小児内分泌学会学術集会
• [Presentation] スンクスの外性器形成過程について． (2018)
  • Author(s): 宮戸真美．
  • Organizer: 第12回スンクス研究会
  • Invited
• [Presentation] NR5A1ミスセンス変異p.R92Wは，ヒトとマウスに共通する46,XY精巣形成不全とヒト特異的46,XX精巣形成を招く． (2017)
  • Author(s): 宮戸真美，乾 雅史，五十嵐麻希，福井由宇子，玉野萌恵，宮戸健二，緒方 勤，高田修治，深見真紀．
  • Organizer: 第21回日本生殖内分泌学会学術集会
  • Place of Presentation: 千里ライフサイエンスセンター（大阪）
  • Year and Date: 2017-01-14
• [Presentation] Mamld1遺伝子欠損は精巣サイズ減少と一日精子産生数減少を招く． (2017)
  • Author(s): 宮戸真美，吉田 薫，宮戸健二，勝見桃理，齊藤和毅，中村 繁，緒方 勤，深見真紀．
  • Organizer: 第40回日本分子生物学会年会、第90回日本生化学会大会 合同大会
• [Presentation] MAMLD1：マウスの分娩開始時期を支配する新たな因子． (2016)
  • Author(s): 宮戸真美．
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川）
  • Year and Date: 2016-11-30
  • Invited
• [Presentation] Genetic knockout of Mamld1 reduces testicular size but permits normal fertility in adult male mice. (2016)
  • Author(s): Miyado M, Yoshida K, Miyado K, Katsumi M, Saito K, Nakamura S, Ogata T and Fukami M.
  • Organizer: The 9th Biannual Meeting of Asia Pacific Pediatric Endocrine Society (APPES) jointly held with the 50th Scientific Meeting of Japanese Society for Pediatric Endocrinology (JSPE)
  • Place of Presentation: 東京国際フォーラム（東京）
  • Year and Date: 2016-10-18
  • Int'l Joint Research