title: Broad, ectopic expression of the sperm protein PLCZ1 induces parthenogenesis and ovarian tumours in mice.
abstract: Mammalian metaphase II (mII) exit and embryogenesis are induced at fertilisation by a signal thought to come from the sperm protein, phospholipase C-zeta (PLCZ1). Meiotic progression can also be triggered without sperm, as in parthenogenesis, although the classic mouse in vivo parthenogenetic model, LT/Sv, fails in meiosis I owing to an unknown molecular etiology. Here, we dissect PLCZ1 specificity and function in vivo and address its ability to interfere with maternal meiotic exit. Wild-type mouse Plcz1 expression was restricted to post-pubertal testes and the brains of both sexes, with region-specifying elements mapping to a 4.1 kb Plcz1 promoter fragment. When broad ectopic PLCZ1 expression was forced in independent transgenic lines, they initially appeared healthy. Their oocytes underwent unperturbed meiotic maturation to mII but subsequently exhibited autonomous intracellular free calcium oscillations, second polar body extrusion, pronucleus formation and parthenogenetic development. Transfer of transgenic cumulus cell nuclei into wild-type oocytes induced activation and development, demonstrating a direct effect of PLCZ1 analogous to fertilisation. Whereas Plcz1 transgenic males remained largely asymptomatic, females developed abdominal swellings caused by benign ovarian teratomas that were under-represented for paternally- and placentally-expressed transcripts. Plcz1 was not overexpressed in the ovaries of LT/Sv or in human germline ovarian tumours. The narrow spectrum of PLCZ1 activity indicates that it is modulated by tissue-restricted accessory factors. This work characterises a novel model in which parthenogenesis and tumourigenesis follow full meiotic maturation and are linked to fertilisation by PLCZ1.
authors.affiliation: Laboratory of Mammalian Molecular Embryology, RIKEN Center for Developmental Biology, 2-2-3 Minatojima Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Yoshida
authors.forename: Manami
authors.initials: M
authors.lastname: Amanai
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fukui
authors.forename: Eriko
authors.initials: E
authors.lastname: Kajikawa
authors.forename: Manjula
authors.initials: M
authors.lastname: Brahmajosyula
authors.forename: Akiko
authors.initials: A
authors.lastname: Iwahori
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Nakano
authors.forename: Shisako
authors.initials: S
authors.lastname: Shoji
authors.forename: Joachim
authors.initials: J
authors.lastname: Diebold
authors.forename: Harald
authors.initials: H
authors.lastname: Hessel
authors.forename: Ralf
authors.initials: R
authors.lastname: Huss
authors.forename: Anthony C F
authors.initials: AC
authors.lastname: Perry
mesh_terms: D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008297:Male; D008540:Meiosis; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010312:Parthenogenesis; D054801:Phosphoinositide Phospholipase C / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013094:Spermatozoa / Q000378:metabolism*
chemical_list: D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; C499235:PLCZ1 protein, human; D054801:Phosphoinositide Phospholipase C; C499234:Plcz1 protein, mouse